Pittsburgh Compound B Positron Emission Tomography Research Articles

Lower Locus Coeruleus Integrity Signals Elevated Entorhinal Tau and Clinical Progression in Asymptomatic Older Individuals.

Elevated entorhinal cortex (EC) tau in low beta-amyloid individuals can predict accumulation of pathology and cognitive decline. We compared the accuracy of magnetic resonance imaging (MRI)-derived locus coeruleus integrity, neocortical beta-amyloid burden by positron emission tomography (PET), and hippocampal volume in identifying elevated entorhinal tau signal in asymptomatic individuals who are considered beta-amyloid PET-negative. We included 188 asymptomatic individuals (70.78 ± 11.51 years, 58% female) who underwent 3T-MRI of the locus coeruleus, Pittsburgh compound-B (PiB), and Flortaucipir (FTP) PET. Associations between elevated EC tau and neocortical PiB, hippocampal volume, or locus coeruleus integrity were evaluated and compared using logistic regression and receiver operating characteristic analyses in the PiB- sample with a clinical dementia rating (CDR) of 0. Associations with clinical progression (CDR-sum-of-boxes) over a time span of 6 years were evaluated with Cox proportional hazard models. We identified 26 (21%) individuals with high EC FTP in the CDR = 0/PiB- sample. Locus coeruleus integrity was a significantly more sensitive and specific predictor of elevated EC FTP (area under the curve [AUC] = 85%) compared with PiB (AUC = 77%) or hippocampal volume (AUC = 76%). Based on the Youden-index, locus coeruleus integrity obtained a sensitivity of 77% and 85% specificity. Using the resulting locus coeruleus Youden cut-off, lower locus coeruleus integrity was associated with a two-fold increase in clinical progression, including mild cognitive impairment. Locus coeruleus integrity has promise as a low-cost, non-invasive screening instrument to detect early cortical tau deposition and associated clinical progression in asymptomatic, low beta-amyloid individuals. ANN NEUROL 2024.

PET/MRI multimodality imaging to evaluate changes in glymphatic system function and biomarkers of Alzheimer’s disease

The glymphatic system is considered to play a pivotal role in the clearance of disease-causing proteins in neurodegenerative diseases. This study employed MR diffusion tensor imaging (DTI) to evaluate glymphatic system function and its correlation with brain amyloid accumulation levels measured using [11C]Pittsburgh compound-B (PiB) PET/MRI. Fifty-six patients with mild cognitive impairment and early Alzheimer’s disease (AD: 70 ± 11 y) underwent [11C]PiB PET/MRI to assess amyloid deposition and were compared with 27 age-matched cognitively normal volunteers (CN: 69 ± 10y). All participants were evaluated for cognitive function using the Mini Mental State Examination (MMSE) before [11C]PiB PET/MRI. DTI images were acquired during the PET/MRI scan with several other MR sequences. The DTI analysis along the perivascular space index (DTI-ALPS index) was calculated to estimate the functional activity of the glymphatic system. Centiloid scale was applied to quantify amyloid deposition levels from [11C]PiB PET images. All patients in the AD group showed positive [11C]PiB accumulation, whereas all CN participants were negative. ALPS-index for all subjects linearly correlated with PiB centiloid, MMSE scores, and hippocampal volume. The correlation between the ALPS-index and PiB accumulation was more pronounced than with any other biomarkers. These findings suggest that glymphatic system dysfunction is a significant factor in the early stages of Alzheimer’s disease.

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.

Patterns of Early Neocortical Amyloid-β Accumulation: A PET Population-Based Study.

The widespread deposition of amyloid-β (Aβ) plaques in late-stage Alzheimer disease is well defined and confirmed by invivo PET. However, there are discrepancies between which regions contribute to the earliest topographic Aβ deposition within the neocortex. Methods: This study investigated Aβ signals in the perithreshold SUV ratio range using Pittsburgh compound B (PiB) PET in a population-based study cross-sectionally and longitudinally. PiB PET scans from 1,088 participants determined the early patterns of PiB loading in the neocortex. Results: Early-stage Aβ loading is seen first in the temporal, cingulate, and occipital regions. Regional early deposition patterns are similar in both apolipoprotein ε4 carriers and noncarriers. Clustering analysis shows groups with different patterns of early amyloid deposition. Conclusion: These findings of initial Aβ deposition patterns may be of significance for diagnostics and understanding the development of Alzheimer disease phenotypes.

Molecular neuroimaging in dominantly inherited versus sporadic early-onset Alzheimer's disease.

Approximately 5% of Alzheimer's disease patients develop symptoms before age 65 (early-onset Alzheimer's disease), with either sporadic (sporadic early-onset Alzheimer's disease) or dominantly inherited (dominantly inherited Alzheimer's disease) presentations. Both sporadic early-onset Alzheimer's disease and dominantly inherited Alzheimer's disease are characterized by brain amyloid-β accumulation, tau tangles, hypometabolism and neurodegeneration, but differences in topography and magnitude of these pathological changes are not fully elucidated. In this study, we directly compared patterns of amyloid-β plaque deposition and glucose hypometabolism in sporadic early-onset Alzheimer's disease and dominantly inherited Alzheimer's disease individuals. Our analysis included 134 symptomatic sporadic early-onset Alzheimer's disease amyloid-Positron Emission Tomography (PET)-positive cases from the University of California, San Francisco, Alzheimer's Disease Research Center (mean ± SD age 59.7 ± 5.6 years), 89 symptomatic dominantly inherited Alzheimer's disease cases (age 45.8 ± 9.3 years) and 102 cognitively unimpaired non-mutation carriers from the Dominantly Inherited Alzheimer Network study (age 44.9 ± 9.2). Each group underwent clinical and cognitive examinations, 11C-labelled Pittsburgh Compound B-PET and structural MRI. 18F-Fluorodeoxyglucose-PET was also available for most participants. Positron Emission Tomography scans from both studies were uniformly processed to obtain a standardized uptake value ratio (PIB50-70 cerebellar grey reference and FDG30-60 pons reference) images. Statistical analyses included pairwise global and voxelwise group comparisons and group-independent component analyses. Analyses were performed also adjusting for covariates including age, sex, Mini-Mental State Examination, apolipoprotein ε4 status and average composite cortical of standardized uptake value ratio. Compared with dominantly inherited Alzheimer's disease, sporadic early-onset Alzheimer's disease participants were older at age of onset (mean ± SD, 54.8 ± 8.2 versus 41.9 ± 8.2, Cohen's d = 1.91), with more years of education (16.4 ± 2.8 versus 13.5 ± 3.2, d = 1) and more likely to be apolipoprotein ε4 carriers (54.6% ε4 versus 28.1%, Cramer's V = 0.26), but similar Mini-Mental State Examination (20.6 ± 6.1 versus 21.2 ± 7.4, d = 0.08). Sporadic early-onset Alzheimer's disease had higher global cortical Pittsburgh Compound B-PET binding (mean ± SD standardized uptake value ratio, 1.92 ± 0.29 versus 1.58 ± 0.44, d = 0.96) and greater global cortical 18F-fluorodeoxyglucose-PET hypometabolism (mean ± SD standardized uptake value ratio, 1.32 ± 0.1 versus 1.39 ± 0.19, d = 0.48) compared with dominantly inherited Alzheimer's disease. Fully adjusted comparisons demonstrated relatively higher Pittsburgh Compound B-PET standardized uptake value ratio in the medial occipital, thalami, basal ganglia and medial/dorsal frontal regions in dominantly inherited Alzheimer's disease versus sporadic early-onset Alzheimer's disease. Sporadic early-onset Alzheimer's disease showed relatively greater 18F-fluorodeoxyglucose-PET hypometabolism in Alzheimer's disease signature temporoparietal regions and caudate nuclei, whereas dominantly inherited Alzheimer's disease showed relatively greater hypometabolism in frontal white matter and pericentral regions. Independent component analyses largely replicated these findings by highlighting common and unique Pittsburgh Compound B-PET and 18F-fluorodeoxyglucose-PET binding patterns. In summary, our findings suggest both common and distinct patterns of amyloid and glucose hypometabolism in sporadic and dominantly inherited early-onset Alzheimer's disease.

Differential Synaptic Loss in β-Amyloid Positive Versus β-Amyloid Negative Corticobasal Syndrome.

The corticobasal syndrome (CBS) is a complex asymmetric movement disorder, with cognitive impairment. Although commonly associated with the primary 4-repeat-tauopathy of corticobasal degeneration, clinicopathological correlation is poor, and a significant proportion is due to Alzheimer's disease (AD). Synaptic loss is a pathological feature of many clinical and preclinical tauopathies. We therefore measured the degree of synaptic loss in patients with CBS and tested whether synaptic loss differed according to β-amyloid status. Twenty-five people with CBS, and 32 age-/sex-/education-matched healthy controls participated. Regional synaptic density was estimated by [11C]UCB-J non-displaceable binding potential (BPND), AD-tau pathology by [18F]AV-1451 BPND, and gray matter volume by T1-weighted magnetic resonance imaging. Participants with CBS had β-amyloid imaging with 11C-labeled Pittsburgh Compound-B ([11C]PiB) positron emission tomography. Symptom severity was assessed with the progressive supranuclear palsy-rating-scale, the cortical basal ganglia functional scale, and the revised Addenbrooke's Cognitive Examination. Regional differences in BPND and gray matter volume between groups were assessed by ANOVA. Compared to controls, patients with CBS had higher [18F]AV-1451 uptake, gray matter volume loss, and reduced synaptic density. Synaptic loss was more severe and widespread in the β-amyloid negative group. Asymmetry of synaptic loss was in line with the clinically most affected side. Distinct patterns of [11C]UCB-J and [18F]AV-1451 binding and gray matter volume loss, indicate differences in the pathogenic mechanisms of CBS according to whether it is associated with the presence of Alzheimer's disease or not. This highlights the potential for different therapeutic strategies in CBSs. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Presenilin-1 mutation position influences amyloidosis, small vessel disease, and dementia with disease stage.

Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin-1 (PSEN1) mutation carriers. We investigated how mutation position relative to codon 200 (pre-/postcodon 200) influences these pathologic features and dementia at different stages. Individuals from families with known PSEN1 mutations (n=393) underwent neuroimaging and clinical assessments. We cross-sectionally evaluated regional Pittsburgh compound B-positron emission tomography uptake, magnetic resonance imaging markers of SVD (diffusion tensor imaging-based white matter injury, white matter hyperintensity volumes, and microhemorrhages), and cognition. Postcodon 200 carriers had lower amyloid burden in all regions but worse markers of SVD and worse Clinical Dementia Rating® scores compared to precodon 200 carriers as a function of estimated years to symptom onset. Markers of SVD partially mediated the mutation position effects on clinical measures. We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials. Mutation position influences Aβ burden, SVD, and dementia. PSEN1 pre-200 group had stronger associations between Aβ burden and disease stage. PSEN1 post-200 group had stronger associations between SVD markers and disease stage. PSEN1 post-200 group had worse dementia score than pre-200 in late disease stage. Diffusion tensor imaging-based SVD markers mediated mutation position effects on dementia in the late stage.

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

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

Harmonizing florbetapir and PiB PET measurements of cortical Aβ plaque burden using multiple regions-of-interest and machine learning techniques: An alternative to the Centiloid approach.

Machine learning (ML) can optimize amyloid (Aβ) comparability among positron emission tomography (PET) radiotracers. Using multi-regional florbetapir (FBP) measures and ML, we report better Pittsburgh compound-B (PiB)/FBP harmonization of mean-cortical Aβ (mcAβ) than Centiloid. PiB-FBP pairs from 92 subjects in www.oasis-brains.org and 46 in www.gaain.org/centiloid-project were used as the training/testing sets. FreeSurfer-extracted FBP multi-regional Aβ and actual PiB mcAβ in the training set were used to train ML models generating synthetic PiB mcAβ. The correlation coefficient (R) between the synthetic/actual PiB mcAβ in the testing set was assessed. In the testing set, the synthetic/actual PiB mcAβ correlation R=0.985 (R2 =0.970) using artificial neural network was significantly higher (p≤6.6e-4) than the FBP/PiB correlation R=0.927 (R2 =0.860), improving total variance percentage (R2 ) from 86% to 97%. Other ML models such as partial least square, ensemble, and relevance vector regressions also improved R (p=9.677e-05 /0.045/0.0017). ML improved mcAβ comparability. Additional studies are needed for the generalizability to other amyloid tracers, and to tau PET. Highlights Centiloid is a calibration of the amyloid scale, not harmonization. Centiloid unifies the amyloid scale without improving inter-tracer association (R2 ). Machine learning (ML) can harmonize the amyloid scale by improving R2 . ML harmonization maps multi-regional florbetapir SUVRs to PiB mean-cortical SUVR. Artificial neural network ML increases Centiloid R2 from 86% to 97%.

Association between physical function and neuroimaging measures in a 2‐year multidomain lifestyle randomized controlled trial

AbstractBackgroundThis exploratory study investigated associations between physical function and 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).MethodFINGER targeted 60–77‐year‐old general population at‐risk and without dementia or substantial cognitive impairment. Measures of physical function (activities of daily living (ADL), hand grip strength, physical performance, Fried’s frailty phenotype index and self‐rated health) from baseline and 2‐year visits were used. Baseline neuroimaging measures, MRI (hippocampus, total gray matter volumes, Alzheimer’s disease (AD) signature cortical thickness) were available for 115‐132 participants and PiB‐PET (composite score) for 44‐48 participants. Linear and logistic regressions were used to test the cross‐sectional associations and the impact of baseline imaging measures on changes in physical function. Models were adjusted for site, sex and education.ResultCross‐sectionally, higher ADL were associated with higher hippocampus volume (β = 0.18 p = 0.048), total gray matter volume (β = 0.15 p = 0.005) and AD signature cortical thickness (β = 0.25 p = 0.006) while stronger hand grip and was associated with higher total gray matter volume (β = 0.20 p = 0.041) significantly. Baseline imaging measures were associated with changes in physical function: higher baseline hippocampus volume was associated with maintenance/improvement in the ADL (OR = 0.56 p = 0.039) while lower hippocampus at baseline predicted poorer physical performance over time (OR = 1.66 p = 0.036).ConclusionHigher brain integrity is associated with better physical function while lower baseline brain integrity predicts poorer physical function over time.

Association between physical function and neuroimaging measures in a 2‐year multidomain lifestyle randomized controlled trial

AbstractBackgroundThis exploratory study investigated associations between physical function and 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).MethodFINGER targeted 60–77‐year‐old general population at‐risk and without dementia or substantial cognitive impairment. Measures of physical function (activities of daily living (ADL), hand grip strength, physical performance, Fried’s frailty phenotype index and self‐rated health) from baseline and 2‐year visits were used. Baseline neuroimaging measures, MRI (hippocampus, total gray matter volumes, Alzheimer’s disease (AD) signature cortical thickness) were available for 115‐132 participants and PiB‐PET (composite score) for 44‐48 participants. Linear and logistic regressions were used to test the cross‐sectional associations and the impact of baseline imaging measures on changes in physical function. Models were adjusted for site, sex and education.ResultCross‐sectionally, higher ADL were associated with higher hippocampus volume (ß = 0.18 p = 0.048), total gray matter volume (ß = 0.15 p = 0.005) and AD signature cortical thickness (ß = 0.25 p = 0.006) while stronger hand grip and was associated with higher total gray matter volume (ß = 0.20 p = 0.041) significantly. Baseline imaging measures were associated with changes in physical function: higher baseline hippocampus volume was associated with maintenance/improvement in the ADL (OR = 0.56 p = 0.039) while lower hippocampus at baseline predicted poorer physical performance over time (OR = 1.66 p = 0.036).ConclusionHigher brain integrity is associated with better physical function while lower baseline brain integrity predicts poorer physical function over time.

Tau pathology relates to regional microstructural alterations of cerebral white matter in older adults with diverse cognitive spectrum

AbstractBackgroundGrowing evidences suggest that degeneration of cerebral white matter (WM) occurs in Alzheimer’s disease (AD) independently of cerebrovascular risks or injury. Previous studies using diffusion tensor imaging (DTI) have reported a loss of WM microstructural integrity in the corpus callosum (CC) and cingulum (CG) in AD dementia and mild cognitive impairment (MCI). However, only limited information is available for the relationship of in vivo AD‐specific pathologies including beta‐amyloid (Aβ) and tau accumulation with WM microstructal alterations. Thus, we aimed to examine the association between in vivo AD pathologies and microstructural integrity of the CC and CG through cross‐sectional and longitudinal approaches.MethodA total of 170 (74 cognitively normal, 58 MCI, and 38 AD dementia) older adults from the Korean Brain Aging Study for the Early diagnosis and prediction of Alzheimer’s disease cohort were included. All participants underwent comprehensive clinical assessment and multi‐modal brain imaging including [11C]‐Pittsburgh‐Compound‐B‐positron emission tomography (PET), 18F‐AV‐1451 PET, and DTI. The mean fractional anisotropy (FA) values were obtained for 2 regions of interests, the CC and CG on DTI. The data was analyzed using linear regression model adjusted for age, sex, APOE4 positivity, and vascular risk factor score. Regression‐based mediation analysis was also conducted to assess the mediation of tau for the relationship between Aβ and FA.ResultIn cross‐sectional analyses for baseline data, global tau deposition had a significant negative association with both CC and CG FA (β = ‐0.013, p = 0.004 and β = ‐0.011, p = 0.002), while global Aβ retention showed a negative association with only CG FA (β = ‐0.015, p = 0.004). Longitudinal analyses revealed that higher tau deposition at baseline was associated with both greater reduction of both CC and CG FA over 2 years (β = ‐0.010, p = 0.001 and β = ‐0.005, p = 0.046), whereas Aβ was associated with neither CC nor CG FA change over the period. Additional mediation analysis demonstrated that the cross‐sectional association between Aβ and CG FA was mediated by tau deposition, while there was no direct relationship between the two.ConclusionOur findings suggest that regional alterations of WM microstructural integrity in MCI and AD dementia, which occurs independently of vascular risks, are mainly related with tau pathology rather than amyloid pathology.

Neuropathological characterization of PiB binding in postmortem striatum in Down syndrome

AbstractBackgroundAmyloid‐beta plaques form in the brain throughout life in people with Down syndrome (DS) and are one of the hallmarks of Alzheimer disease (AD) neuropathology. The regional progression of amyloid buildup in DS is similar to that of late onset AD (LOAD) in the neurotypical population. The development of positron emission tomography (PET) ligands like Pittsburgh Compound B (PiB) has allowed researchers and clinicians to visualize and track amyloid accumulation in the brain throughout life. Using this technology, a unique pattern emerges in people with DS, where the earliest and strongest PiB PET retention is in the striatum, unlike LOAD but similar to autosomal dominant AD. Frontal cortex PiB PET retention is similar in all groups. We used a fluorescent derivative of PiB, cyano‐PiB (CN‐PiB), to investigate PiB labeling postmortem in DS striatum. We hypothesized that striatal CN‐PiB load increases with age and is greater than in the frontal cortex, similar to observations from PiB PET studies of adults with DS.MethodWe conducted CN‐PiB labeling in postmortem striatum and frontal cortex from 44 cases with DS ages ranging from 42 to 70 years (25F/19M, mean PMI 7.4 hours). Whole slide imaging and automated image analysis were used to derive individual plaque‐level information regarding load, size, and distribution of CN‐PiB+ plaques in DS with age.ResultCN‐PiB labeled plaques in both the striatum and frontal cortex were also positive for amyloid‐beta antibodies targeting epitopes 1‐16, 17‐24, and x‐42. Preliminary data suggest that striatal CN‐PiB load (median = 2.3%) is not higher compared to the frontal cortex in DS (median = 10%). Striatal CN‐PiB load did not change with age from 42 to 70 years, suggesting an early saturation (IQR = 3.5%).ConclusionCN‐PiB labeled amyloid‐beta plaque load in the striatum in DS is comparable to conventional neuropathologic analysis and does not differ from frontal cortical load. Other aspects of PiB‐binding or pathologies may contribute to the early and prominent striatal PiB PET retention reported in DS. It will be important in future studies to include younger cases with DS.

Significance of a positive tau pet scan with a negative amyloid pet scan

AbstractBackgroundThe implications of a positive tau (T) Positron Emission Tomography (PET) with a negative beta amyloid (A) PET are not well understood. We investigated cognitive performance in participants who were positive on tau PET but negative on beta amyloid PET.MethodWe evaluated 98 participants from the Mayo Clinic Study of Aging (MCSA) and the Mayo Clinic Alzheimer’s Disease Research Center (ADRC) who were positive for Flortaucipir (FTP) and negative for PiB PET. Participants were classified as A‐ and T+ based on Standardized Uptake Value Ratios (SUVr) of FTP and PiB PET scans, and were matched 2:1 to amyloid negative and tau negative cognitively unimpaired controls from the MCSA. Cognitive test scores were compared between the combined ADRC/MCSA group and MCSA only group. We also examined clinical diagnoses in our cohort. The most common were Alzheimer’s Disease, mild cognitive impairment (MCI), Dementia with Lewy Bodies (DLB) and Frontotemporal dementia (FTD) amongst others.ResultThere were no significant differences in demographic features or PiB SUVr between groups. There were significant differences in APOE genotype between groups. In the combined ADRC/MCSA group, 25% of A‐T‐ and 13% of A‐T+ were APOE e4 carriers (p = 0.016), and in the MCSA only group, 27% of A‐T‐and 10% of A‐T+ were APOE e4 carriers (p = 0.010). In the combined ADRC/MCSA group, the A‐T+ group demonstrated lower performance than the A‐T‐ group on the Mini Mental Status Exam (MMSE) (p&lt;0.001), Wechsler Memory Scale‐Revised Logical Memory I (p&lt;0.001) and Logical Memory II (p&lt;0.001), Auditory verbal Learning Test Delayed Recall (AVLT) (p = 0.004), Category fluency animals (p = 0.005), Category fluency vegetables (p = 0.021), Trailmaking test A (p&lt;0.001), Trail making test B (p&lt;0.001), Wechsler Adult Intelligence Scale‐IV (WAIS‐IV) (p = 0.002), and Unified Parkinson’s Disease Rating Scale part III (UPDRS III) (p = 0.003). In the MCSA only group, the A‐T+ group had lower scores on Logical Memory II (p = 0.022), AVLT delated recall (p = 0.04), and WAIS‐R block design (p = 0.035) compared to the A‐T‐group.ConclusionPositive tau PET in the absence of beta‐amyloid positivity is associated with lower cognitive performance.

Race, inflammation, and amyloid deposition in Black/African American and Non‐Hispanic White older adults

AbstractBackgroundBlack/African American (AA) older adults are twice as likely as Non‐Hispanic White (NHW) older adults to be diagnosed with Alzheimer’s Disease (AD) and related dementias. Inflammation and brain beta‐amyloid (Ab) may play a differential role in AD pathophysiology in AA and NHW older adults. We hypothesized that there would be racialized group differences in inflammation, amyloid deposition, and everyday discrimination.MethodOne hundred and ninety‐eight participants (Table 1) were recruited in Pittsburgh, PA and the surrounding areas as a part of the Human Connectome Project. Blood‐based biomarkers of inflammatory markers interleukin 6 (IL6) and tumor necrosis factor alpha (TNFa) were examined. Brain Ab was quantified using Pittsburgh Compound‐B (PiB) Positron Emission Tomography (PET) imaging standardized uptake value ratio (SUVr). Experiences of discrimination were measured on a subset of 66 participants (mean age = 62.62±9.37 years, 46.97% AA) using the Everyday Discrimination Scale (EDS). Analysis of covariance, controlling for age, were conducted to examine the racialized group differences for TNFa, IL6, Ab SUVr. Independent samples t‐tests were conducted to compare EDS by racialized group.ResultParticipants. AA participants were on average 6.58 years younger than NHW participants and more likely to have a clinical diagnosis of impaired without complaints, mild cognitive impairment (MCI), or AD (all p’s&lt;.05) (Table 1). Additionally, in the subset of participants with EDS data, AA participants experienced higher total discrimination than NHW participants (p&lt;.05).Inflammation. NHW participants had higher TNFa inflammation levels than AA participants (p = .029). No differences by racialized group were observed for IL6.PiB‐PET. The frequency of amyloid positivity was higher in NHW than AA participants (p = &lt;.001). Global Ab SUVr was higher in NHW than AA participants (p&lt;.05).ConclusionThe results from this study provide evidence of higher peripheral blood inflammation and PiB PET binding in NHW than AA participants, but higher likelihood of clinical diagnoses and more experiences of discrimination in the AA than in NHW participants. Future investigation of these racialized differences as they relate to age and other determinants of health are needed.

The value of FDG combined with PiB PET in the diagnosis of patients with cognitive impairment in a memory clinic.

To analyze the value of 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) combined with amyloid PET in cognitive impairment diagnosis. A total of 187 patients with dementia or mild cognitive impairment (MCI) who underwent 11 C-Pittsburgh compound B (PiB) and FDG PET scans in a memory clinic were included in the final analysis. Amyloid-positive and amyloid-negative dementia patient groups showed a significant difference in the proportion of individuals presenting temporoparietal cortex (p < 0.001) and posterior cingulate/precuneus cortex (p < 0.001) hypometabolism. The sensitivity and specificity of this hypometabolic pattern for identifying amyloid pathology were 72.61% and 77.97%, respectively, in patients clinically diagnosed with AD and 60.87% and 76.19%, respectively, in patients with MCI. The initial diagnosis was changed in 32.17% of patients with dementia after considering both PiB and FDG results. There was a significant difference in both the proportion of patients showing the hypometabolic pattern and PiB positivity between dementia conversion patients and patients with a stable diagnosis of MCI (p < 0.05). Temporoparietal and posterior cingulate/precuneus cortex hypometabolism on FDG PET suggested amyloid pathology in patients with cognitive impairment and is helpful in diagnostic decision-making and predicting AD dementia conversion from MCI, particularly when combined with amyloid PET.

A Multivariate Method for Estimating and comparing whole brain functional connectomes from fMRI and PET data.

Positron emission tomography (PET) and magnetic resonance imaging (MRI) are two commonly used imaging techniques to visualize brain function. The use of inter-network covariation (a functional connectome) is a widely used approach to infer links among different brain networks. While whole brain resting fMRI connectomes are widely used, PET data has mostly been analyzed using a few regions of interest. There has been much less work estimating PET spatial networks and almost no work on their connectivity (covariation) in the context of a whole brain data-driven connectome, nor have there been direct comparisons between whole brain PET and fMRI connectomes. Here we present an approach to leverage spatially constrained ICA to compute an estimate of the PET connectome. Results reveal highly modularized connectome patterns that are complementary to that identified from resting fMRI. Similarly, we were able to identify comparable resting networks from a PiB PET scan that can be directly compared to networks in rest fMRI data and results reveal similar, but not identical, network spatial patterns, with the PET networks being slightly smoother and, in some cases, showing variations in subnodes. The resulting networks, decomposed into spatial maps and subject expressions (loading parameters) linked to resting fMRI provide a new way to evaluate the complementary information in PET and fMRI and open up new possibilities for biomarker development.Clinical Relevance-This study analyzes the whole-brain PET and fMRI connectomes, capturing the complementary information from both imaging modalities, thereby introducing a new scope for biomarker development.

Poorer aging trajectories are associated with elevated serotonin synthesis capacity.

The dorsal raphe nucleus (DRN) is one of the earliest targets of Alzheimer's disease-related tau pathology and is a major source of brain serotonin. We used [18F]Fluoro-m-tyrosine ([18F]FMT) PET imaging to measure serotonin synthesis capacity in the DRN in 111 healthy adults (18-85 years-old). Similar to reports in catecholamine systems, we found elevated serotonin synthesis capacity in older adults relative to young. To establish the structural and functional context within which serotonin synthesis capacity is elevated in aging, we examined relationships among DRN [18F]FMT net tracer influx (Ki) and longitudinal changes in cortical thickness using magnetic resonance imaging, longitudinal changes in self-reported depression symptoms, and AD-related tau and β-amyloid (Aβ) pathology using cross-sectional [18F]Flortaucipir and [11C]Pittsburgh compound-B PET respectively. Together, our findings point to elevated DRN [18F]FMT Ki as a marker of poorer aging trajectories. Older adults with highest serotonin synthesis capacity showed greatest temporal lobe cortical atrophy. Cortical atrophy was associated with increasing depression symptoms over time, and these effects appeared to be strongest in individuals with highest serotonin synthesis capacity. We did not find direct relationships between serotonin synthesis capacity and AD-related pathology. Exploratory analyses revealed nuanced effects of sex within the older adult group. Older adult females showed the highest DRN synthesis capacity and exhibited the strongest relationships between entorhinal cortex tau pathology and increasing depression symptoms. Together these findings reveal PET measurement of the serotonin system to be a promising marker of aging trajectories relevant to both AD and affective changes in older age.

Sex differences in the progression of glucose metabolism dysfunction in Alzheimer’s disease

Alzheimer’s disease (AD) is a common neurodegenerative disease characterized by amyloid plaques and impaired brain metabolism. Because women have a higher prevalence of AD than men, sex differences are of great interest. Using cross-sectional and longitudinal data, we showed sex-dependent metabolic dysregulations in the brains of AD patients. Cohort 1 (South Korean, n = 181) underwent Pittsburgh compound B-PET, fluorodeoxyglucose-PET, magnetic resonance imaging, and blood biomarker (plasma tau and beta-amyloid 42 and 40) measurements at baseline and two-year follow-ups. Transcriptome analysis of data from Cohorts 2 and 3 (European, n = 78; Singaporean, n = 18) revealed sex differences in AD-related alterations in brain metabolism. In women (but not in men), all imaging indicators displayed consistent correlation curves with AD progression. At the two-year follow-up, clear brain metabolic impairment was revealed only in women, and the plasma beta-amyloid 42/40 ratio was a possible biomarker for brain metabolism in women. Furthermore, our transcriptome analysis revealed sex differences in transcriptomes and metabolism in the brains of AD patients as well as a molecular network of 25 female-specific glucose metabolic genes (FGGs). We discovered four key-attractor FGG genes (ALDOA, ENO2, PRKACB, and PPP2R5D) that were associated with amyloid/tau-related genes (APP, MAPT, BACE1, and BACE2). Furthermore, these genes successfully distinguished amyloid positivity in women. Understanding sex differences in the pathogenesis of AD and considering these differences will improve development of effective diagnostics and therapeutic treatments for AD.

Prediction of Longitudinal Cognitive Decline in Preclinical Alzheimer Disease Using Plasma Biomarkers

Alzheimer disease (AD) pathology starts with a prolonged phase of β-amyloid (Aβ) accumulation without symptoms. The duration of this phase differs greatly among individuals. While this disease phase has high relevance for clinical trial designs, it is currently unclear how to best predict the onset of clinical progression. To evaluate combinations of different plasma biomarkers for predicting cognitive decline in Aβ-positive cognitively unimpaired (CU) individuals. This prospective population-based prognostic study evaluated data from 2 prospective longitudinal cohort studies (the Swedish BioFINDER-1 and the Wisconsin Registry for Alzheimer Prevention [WRAP]), with data collected from February 8, 2010, to October 21, 2020, for the BioFINDER-1 cohort and from August 11, 2011, to June 27, 2021, for the WRAP cohort. Participants were CU individuals recruited from memory clinics who had brain Aβ pathology defined by cerebrospinal fluid (CSF) Aβ42/40 in the BioFINDER-1 study and by Pittsburgh Compound B (PiB) positron emission tomography (PET) in the WRAP study. A total of 564 eligible Aβ-positive and Aβ-negative CU participants with available relevant data from the BioFINDER-1 and WRAP cohorts were included in the study; of those, 171 Aβ-positive participants were included in the main analyses. Baseline P-tau181, P-tau217, P-tau231, glial fibrillary filament protein, and neurofilament light measured in plasma; CSF biomarkers in the BioFINDER-1 cohort, and PiB PET uptake in the WRAP cohort. The primary outcome was longitudinal measures of cognition (using the Mini-Mental State Examination [MMSE] and the modified Preclinical Alzheimer Cognitive Composite [mPACC]) over a median of 6 years (range, 2-10 years). The secondary outcome was conversion to AD dementia. Baseline biomarkers were used in linear regression models to predict rates of longitudinal cognitive change (calculated separately). Models were adjusted for age, sex, years of education, apolipoprotein E ε4 allele status, and baseline cognition. Multivariable models were compared based on model R2 coefficients and corrected Akaike information criterion. Among 171 Aβ-positive CU participants included in the main analyses, 119 (mean [SD] age, 73.0 [5.4] years; 60.5% female) were from the BioFINDER-1 study, and 52 (mean [SD] age, 64.4 [4.6] years; 65.4% female) were from the WRAP study. In the BioFINDER-1 cohort, plasma P-tau217 was the best marker to predict cognitive decline in the mPACC (model R2 = 0.41) and the MMSE (model R2 = 0.34) and was superior to the covariates-only models (mPACC: R2 = 0.23; MMSE: R2 = 0.04; P < .001 for both comparisons). Results were validated in the WRAP cohort; for example, plasma P-tau217 was associated with mPACC slopes (R2 = 0.13 vs 0.01 in the covariates-only model; P = .01) and MMSE slopes (R2 = 0.29 vs 0.24 in the covariates-only model; P = .046). Sparse models were identified with plasma P-tau217 as a predictor of cognitive decline. Power calculations for enrichment in hypothetical clinical trials revealed large relative reductions in sample sizes when using plasma P-tau217 to enrich for CU individuals likely to experience cognitive decline over time. In this study, plasma P-tau217 predicted cognitive decline in patients with preclinical AD. These findings suggest that plasma P-tau217 may be used as a complement to CSF or PET for participant selection in clinical trials of novel disease-modifying treatments.