Pittsburgh Compound B Uptake Research Articles

Cross-sectional and longitudinal comparisons of biomarkers and cognition among asymptomatic middle-aged individuals with a parental history of either autosomal dominant or late-onset Alzheimer's disease.

Comparisons of late-onset Alzheimer's disease (LOAD) and autosomal dominant AD (ADAD) are confounded by age. We compared biomarkers from cerebrospinal fluid (CSF), magnetic resonance imaging, and amyloid imaging with Pittsburgh Compound-B (PiB) across four groups of 387 cognitively normal participants, 42 to 65 years of age, in the Dominantly Inherited Alzheimer Network (DIAN) and the Adult Children Study (ACS) of LOAD: DIAN mutation carriers (MCs) and non-carriers (NON-MCs), and ACS participants with a positive (FH+) and negative (FH-) family history of LOAD. At baseline, MCs had the lowest age-adjusted level of CSF Aβ42 and the highest levels of total and phosphorylated tau-181, and PiB uptake. Longitudinally, MC had similar increase in PiB uptake to FH+, but drastically faster decline in hippocampal volume than others, and was the only group showing cognitive decline. Preclinical ADAD and LOAD share many biomarker signatures, but cross-sectional and longitudinal differences may exist.

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.

Regional beta‐amyloid and tau deposition: Results from the Framingham Heart Study

AbstractBackgroundThe Framingham Heart Study (FHS), a three‐generation community‐based cohort studying cardiovascular disease across the adult lifespan, has expanded to include positron emission tomography (PET) of beta‐amyloid (Aβ) and tau. Our aim is to characterize these pathologies in this unique sample and utilize the wide age range to assess the spatiotemporal ordering of emerging Aβ and tau.Method211 clinically‐normal adults aged 33‐74 from FHS underwent Pittsburgh Compound B (PIB) and Flortaucipir (FTP) PET. PIB and FTP were regionally quantified in Desikan regions using distribution volume ratio (DVR) for PIB and standardized uptake volume ratio (SUVR) for FTP. Three approaches were used to identify early accumulating regions: 1. A series of Age*APOE linear models to identify regions accumulating earlier in the lifespan in ε4 carriers. 2. Identification of early regions as those more frequently elevated as previously used in older adults, with Gaussian mixture models (GMM) conducted to evaluate bimodality and set biomarker positivity thresholds for each region. 3. Applied the same frequency approach using well‐validated PIB GMM thresholds based on older adults from the Harvard Aging Brain Study (HABS).ResultFor PIB, significant Age*APOE interactions (Fig. 1) were seen across multiple regions previously implicated as early‐accumulating based on elevation frequencies from older adult samples, as well as the pars opercularis (p=0.005) and lateral parietal cortices (p<0.04). PIB was significantly bimodal across all ROIs (LRT>36.1, p<0.001; Fig. 1). Application of GMM‐based regional positivity frequencies derived within FHS versus from HABS thresholds led to substantial discrepancies in the spatiotemporal ordering of PIB (rs=0.30, p=0.17).Age*APOE effects were not detected for any tau regions, but inferior temporal (IT), middle temporal (MT), and amygdala (AM) increased with age (Fig. 2). Higher global Aβ was also associated with higher FTP SUVR in IT, MT, and a trend for AM, as well as inferior parietal and precuneus (Fig. 2).ConclusionAβ and tau mainly follow spatiotemporal patterns consistent with prior evidence in older adult samples. GMM‐based methods used in older adult samples to dichotomize biomarker positivity may be suboptimal in younger samples. Continuous approaches may better capture early Aβ and tau in younger populations.

Cross-Sectional and Longitudinal Comparisons of Biomarkers and Cognition Among Asymptomatic Middle-Aged Individuals with a Parental History of Either Autosomal Dominant or Late Onset Alzheimer Disease

Background: The comparison of autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD) is almost perfectly confounded by age, leading to a major challenge in the interpretation of results. We aim to compare biomarkers from the cerebrospinal fluid (CSF) and neuroimaging (magnetic resonance imaging (MRI); amyloid Positron Emission Tomography (PET)) between age-matched asymptomatic individuals at-risk for ADAD or LOAD. Methods: Cross-sectional and longitudinal biomarker and cognitive data from asymptomatic participants of 42 to 65 years in the Dominantly Inherited Alzheimer Network (DIAN) and the Washington University Adult Children Study (ACS) of LOAD were analyzed across 4 groups: DIAN mutation carriers (MC, n=33) and non-carriers (NON-MC, n=58), and ACS participants with a positive (FH+, n=176) and negative family history (FH-, n=120) of LOAD. Findings: Baseline age had the strongest effect on β-amyloid load (via Pittsburgh Compound B (PIB) PET) in DIAN MC, and was significantly associated with cortical thickness for all except for DIAN NON-MC. At the mean baseline age, DIAN MC had the lowest levels of CSF Aβ42, the highest levels of CSF total Tau, phosphorylated Tau (pTau181), and PIB PET uptake. Longitudinally, DIAN NON-MC showed no significant changes in any markers, whereas DIAN MC showed significant changes in all but CSF markers. ACS FH+ and FH- both showed significant changes in CSF Aβ42 and PIB uptake. DIAN MC had similar rate of increase in PIB PET uptake to ACS FH+, drastically faster rate of decline in hippocampal volume than others, and was the only group showing significant cognitive decline. Interpretation: Preclinical ADAD and LOAD appear to share many biomarker signatures, but significant differences between preclinical ADAD and ACS FH+ were found at baseline, and on the longitudinal changes in hippocampal volume and cognition, likely due to the later preclinical stage of ADAD at the similar ages. Funding: This study was supported by National Institute on Aging (NIA) grant R01 AG053550 (Dr. Xiong) and NIA grants P50 AG005681, P01AG026276, and P01 AG0399131 (Dr. Morris), and UF1AG032438 (Dr. Bateman). Image processing was supported in part by the Neuroimaging Informatics and Analysis Center (1P30NS098577) and R01 EB009352 (Benzinger). Data collection and sharing for this project was partly supported by The Dominantly Inherited Alzheimer’s Network (DIAN, UF1AG032438) funded by the National Institute on Aging (NIA), the German Center for Neurodegenerative Diseases (DZNE), Raul Carrea Institute for Neurological Research (FLENI), Partial support by Japan Agency for Medical Research and Development (AMED) JP21dk0207049 (Dr. Ikeuchi), and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) Declaration of Interest: All the authors declare no competing interest. Ethical Approval: The WU Human Research Protection Office approved both the ACS and the DIAN, the Institutional Review Boards/Independent Ethics Committees approved the DIAN protocol at all DIAN sites, and all participants gave written informed consent.

Multiple sclerosis is associated with lower amyloid but normal tau burden on PET

AbstractBackgroundWhile β‐amyloid and tau PET imaging are widely studied in cognitive aging and Alzheimer’s disease (AD), little is known about findings in aging multiple sclerosis (MS) patients. As aging is an essential factor in developing neurodegeneration in MS, β‐amyloid and tau biomarkers may be utilized to understand the influence of AD pathophysiology on cognitive aging in MS.MethodWe studied patients with MS (n=16) and controls (n=80) matched for age, sex and APOE ε4 status from the population‐based Mayo Clinic Study of Aging who underwent Pittsburgh compound‐B (PiB) PET imaging. Twelve of the 16 patients with MS and 60 matching controls also underwent flortaucipir (AV1451) tau PET. Cortical PiB and AV1451 standard uptake value ratios (SUVr) from previously determined AD signature regions and from the entire cortex were calculated for group comparisons and testing for associations with age.ResultAD signature PiB SUVr (p=0.044), total cortical PiB SUVr (p=0.048) and the frequency of abnormal PiB SUVrs (p=0.040) were lower in patients with MS than controls. Although AD signature and total cortical AV1451 SUVrs were not different between the groups, the frequency of abnormal AV1451 SUVrs was higher (p=0.041) in patients with MS than controls. The association of AD signature PiB SUVr with age was steeper in the controls compared to patients with MS (p=0.002). Similarly, the association of total cortical PiB SUVr with age was steeper in the controls compared to patients with MS (p=0.002). There was no difference in the association of AV1451 SUVr findings with age between the MS patients and controls (Figure 1). The AD signature PiB SUVr increased more with increasing AD signature AV1451 SUVr in controls than in patients with MS (p=0.03) (Figure 2).ConclusionIn patients with MS, cortical β‐amyloid deposition was lower than age‐matched controls, while cortical tau deposition was not different between the groups. This suggests that some aspect of MS pathobiology retards the accumulation of β‐amyloid, but not the accumulation of tau.

Imaging Biomarkers of Alzheimer Disease in Multiple Sclerosis.

ObjectiveTo investigate β‐amyloid and tau depositions using Pittsburgh compound B (PiB) positron emission tomography (PET) and AV1451 tau PET imaging in aging multiple sclerosis (MS) patients.MethodsPatients with MS (n = 16) and controls (n = 80) matched for age, sex, and APOE ε4 status from the population‐based Mayo Clinic Study of Aging who underwent PiB PET imaging were studied. Of these individuals, 12 patients with MS and 60 matching controls also underwent AV1451 tau PET. Cortical PiB and AV1451 standard uptake value ratios (SUVrs) from the entire cortex and previously determined Alzheimer disease (AD) signature regions in the same population were calculated for group comparisons and testing for associations with age.ResultsAD signature PiB SUVr (odds ratio [OR] [95% confidence interval (CI)] = 0.52 [0.27–0.98], p = 0.044), total cortical PiB SUVr (OR [95% CI] = 0.52 [0.28–0.99], p = 0.048), and the frequency of abnormal PiB SUVrs (OR [95% CI] = 0.10 [0.01–0.90], p = 0.040) were lower in MS than controls. Although AD‐signature and total cortical AV1451 SUVrs were not different between the groups, the frequency of abnormal AV1451 SUVrs was higher (OR [95% CI] = 10.65 [1.10–103.35], p = 0.041) in MS than controls. The association of AD signature PiB SUVr with age was steeper in the controls compared to patients with MS (estimate [95% CI] = −0.14 [−0.023 to −0.006], p = 0.002). Similarly, the association of total cortical PiB SUVr with age was steeper in the controls compared to patients with MS (estimate [95% CI] = −0.13 [−0.021 to −0.005], p = 0.002). There was no difference in the association of AV1451 SUVr findings with age between the MS patients and controls.InterpretationAlthough both β‐amyloid and tau are biomarkers of cognitive aging and AD, cortical β‐amyloid deposition was lower in MS than age‐matched controls, suggesting that some aspect of MS pathobiology retards the accumulation of β‐amyloid but not the accumulation of tau. ANN NEUROL 2020;87:556–567

Relationship Between PET-Assessed Amyloid Burden and Visual and Verbal Episodic Memory Performance in Elderly Subjects.

Studies of elderly subjects using biomarkers that are proxies for Alzheimer's disease (AD) pathology have the potential to document meaningful relationships between cognitive performance and biomarker changes along the AD continuum. To document cognitive performance differences across distinct AD stages using a categorization based on the presence of PET-assessed amyloid-β (Aβ) burden and neurodegeneration. Patients with mild dementia compatible with AD (n = 38) or amnestic mild cognitive impairment (aMCI; n = 43) and a cognitively unimpaired group (n = 27) underwent PET with Pittsburgh compound-B (PiB) assessing Aβ aggregation (A+) and [18F]FDG-PET assessing neurodegeneration ((N)+). Cognitive performance was assessed with verbal and visual episodic memory tests and the Mini-Mental State Examination. The A+(N)+ subgroup (n = 32) showed decreased (p < 0.001) cognitive test scores compared to both A+(N)-(n = 18) and A-(N)-(n = 49) subjects, who presented highly similar mean cognitive scores. Despite its modest size (n = 9), the A-(N)+ subgroup showed lower (p < 0.043) verbal memory scores relative to A-(N)-subjects, and trend lower (p = 0.096) scores relative to A+(N)-subjects. Continuous Aβ measures (standard uptake value ratios of PiB uptake) were correlated most significantly with visual memory scores both in the overall sample and when analyses were restricted to dementia or (N)+ subjects, but not in non-dementia or (N)-groups. These results demonstrate that significant Aβ-cognition relationships are highly salient at disease stages involving neurodegeneration. The fact that findings relating Aβ burden to memory performance were detected only at (N)+ stages, together with the similarity of test scores between A+(N)-and A-(N)-subjects, reinforce the view that Aβ-cognition relationships during early AD stages may remain undetectable unless substantially large samples are evaluated.

Flotillin is a Novel Diagnostic Blood Marker of Alzheimer's Disease.

Currently, best-characterized indicators for Alzheimer's disease (AD) diagnosis are the decreased levels of amyloid-β protein 42 and increased levels of phosphorylated tau in cerebrospinal fluid (CSF). The positron emission tomography (PET) imaging with Pittsburgh compound B (PiB) is also used in AD diagnosis by visualizing amyloid deposition in the brain. These methods are invasive or expensive; therefore, less invasive and easily detectable blood biomarkers are required. Because our previous study showed that flotillin release, a marker of exosomes, was attenuated by Aβ, we designed the present study to determine whether flotillin level could be reduced in CSF and/or serum of patients with AD. In this study, we analyzed flotillin levels in CSF and serum of non-AD controls, patients with AD and mild cognitive impairment (MCI) by western blotting. Flotillin levels in cerebroventricular fluid (CVF) and serum of AD, vascular dementia (VaD), and non-AD autopsy cases were also analyzed. Flotillin levels significantly decreased in the CSF and serum of AD patients compared with those of non-AD controls, respectively. Moreover, in patients with MCI due to AD determined by PiB-PET, CSF and serum flotillin levels significantly decreased compared with those of patients with MCI due to non-AD. Flotillin levels remained unchanged in CVF and serum of autopsy cases diagnosed as VaD. Serum flotillin level is negatively associated with brain amyloid deposition indicated as PiB uptake. These results demonstrate that serum flotillin level can serve as one of the blood markers for estimation of brain amyloid deposition and early diagnosis of AD.

Amyloid and cerebrovascular burden divergently influence brain functional network changes over time.

To examine the effects of baseline Alzheimer disease and cerebrovascular disease markers on longitudinal default mode network (DMN) and executive control network (ECN) functional connectivity (FC) changes in mild cognitive impairment (MCI). We studied 30 patients with amnestic MCI (aMCI) and 55 patients with subcortical vascular MCI (svMCI) with baseline Pittsburgh Compound B (PiB)-PET scans and longitudinal MRI scans. Participants were followed up clinically with annual MRI for up to 4 years (aMCI: 26 with 2 timepoints, 4 with 3 timepoints; svMCI: 13 with 2 timepoints, 16 with 3 timepoints, 26 with 4 timepoints). β-Amyloid (Aβ) burden was associated with longitudinal DMN FC declines, while cerebrovascular burden was associated with longitudinal ECN FC changes. When patients were divided into PiB+ and PiB- groups, PiB+ patients showed longitudinal DMN FC declines, while patients with svMCI showed longitudinal ECN FC increases. Direct comparisons between the 2 groups without mixed pathology (aMCI PiB+ and svMCI PiB-) recapitulated this divergent pattern: aMCI PiB+ patients showed steeper longitudinal DMN FC declines, while svMCI PiB- patients showed steeper longitudinal ECN FC increases. Finally, using baseline PiB uptake and lacune numbers as continuous variables, baseline PiB uptake showed inverse U-shape associations with longitudinal DMN FC changes in both MCI subtypes, while baseline lacune numbers showed mainly inverse U-shape relationships with longitudinal ECN FC changes in patients with svMCI. Our findings underscore the divergent effects of Aβ and cerebrovascular burden on longitudinal FC changes in the DMN and ECN in the predementia stage, which reflect the underlying pathology and may be used to track early changes in Alzheimer disease and cerebrovascular disease.

Investigation of white matter PiB uptake as a marker of white matter integrity.

ObjectiveTo investigate the associations of Pittsburgh compound‐B (PiB) uptake in white matter hyperintensities (WMH) and normal appearing white matter (NAWM) with white matter (WM) integrity measured with DTI and cognitive function in cognitively unimpaired older adults.MethodsCognitively unimpaired older adults from the population‐based Mayo Clinic Study of Aging (n = 537, age 65–95) who underwent both PiB PET and DTI were included. The associations of WM PiB standard uptake value ratio (SUVr) with fractional anisotropy (FA) and mean diffusivity (MD) in the WMH and NAWM were tested after adjusting for age. The associations of PiB SUVr with cognitive function z‐scores were tested after adjusting for age and global cortical PiB SUVr.ResultsThe WMH PiB SUVr was lower than NAWM PiB SUVr (P < 0.001). In the WMH, lower PiB SUVr correlated with lower FA (r = 0.21, P < 0.001), and higher MD (r = −0.31, P < 0.001). In the NAWM, lower PiB SUVr only correlated with higher MD (r = −0.10, P = 0.02). Both in the WMH and NAWM, lower PiB SUVr was associated with lower memory, language, and global cognitive function z‐scores after adjusting for age and global cortical PiB SUVr.InterpretationReduced PiB uptake in the WMH is associated with a loss of WM integrity and cognitive function after accounting for the global cortical PiB uptake, suggesting that WM PiB uptake may be an early biomarker of WM integrity that precedes cognitive impairment in older adults. When using WM as a reference region in cross‐sectional analysis of PiB SUVr, individual variability in WMH volume as well as age should be considered.

Relative cerebral flow from dynamic PIB scans as an alternative for FDG scans in Alzheimer's disease PET studies.

In Alzheimer’s Disease (AD) dual-tracer positron emission tomography (PET) studies with 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) and 11C-labelled Pittsburgh Compound B (PIB) are used to assess metabolism and cerebral amyloid-β deposition, respectively. Regional cerebral metabolism and blood flow (rCBF) are closely coupled, both providing an index for neuronal function. The present study compared PIB-derived rCBF, estimated by the ratio of tracer influx in target regions relative to reference region (R1) and early-stage PIB uptake (ePIB), to FDG scans. Fifteen PIB positive (+) patients and fifteen PIB negative (-) subjects underwent both FDG and PIB PET scans to assess the use of R1 and ePIB as a surrogate for FDG. First, subjects were classified based on visual inspection of the PIB PET images. Then, discriminative performance (PIB+ versus PIB-) of rCBF methods were compared to normalized regional FDG uptake. Strong positive correlations were found between analyses, suggesting that PIB-derived rCBF provides information that is closely related to what can be seen on FDG scans. Yet group related differences between method’s distributions were seen as well. Also, a better correlation with FDG was found for R1 than for ePIB. Further studies are needed to validate the use of R1 as an alternative for FDG studies in clinical applications.

Brain β-Amyloid and Atrophy in Individuals at Increased Risk of Cognitive Decline.

The relationship between brain β-amyloid and regional atrophy is still incompletely understood in elderly individuals at risk of dementia. Here, we studied the associations between brain β-amyloid load and regional GM and WM volumes in older adults who were clinically evaluated as being at increased risk of cognitive decline based on cardiovascular risk factors. Forty subjects (63-81 years of age) were recruited as part of a larger study, the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability. Neuroimaging consisted of PET using 11C Pittsburgh compound-B and T1-weighted 3D MR imaging for the measurement of brain β-amyloid and GM and WM volumes, respectively. All subjects underwent clinical, genetic, and neuropsychological evaluations for the assessment of cognitive function and the identification of cardiovascular risk factors. Sixteen subjects were visually evaluated as showing cortical β-amyloid (positive for β-amyloid). In the voxel-by-voxel analyses, no significant differences were found in GM and WM volumes between the samples positive and negative for β-amyloid. However, in the sample positive for β-amyloid, increases in 11C Pittsburgh compound-B uptake were associated with reductions in GM volume in the left prefrontal (P = .02) and right temporal lobes (P = .04). Our results show a significant association between increases in brain β-amyloid and reductions in regional GM volume in individuals at increased risk of cognitive decline. This evidence is consistent with a model in which increases in β-amyloid incite neurodegeneration in memory systems before cognitive impairment manifests.

Longitudinal cortical thinning and cognitive decline in patients with early- versus late-stage subcortical vascular mild cognitive impairment.

Biomarker changes in cognitively impaired patients with small vessel disease are largely unknown. The rate of amyloid/lacune progression, cortical thinning and cognitive decline were evaluated in subcortical vascular mild cognitive impairment (svMCI) patients. Seventy-two svMCI patients were divided into early stage (ES-svMCI, n = 39) and late stage (LS-svMCI, n = 33) according to their Clinical Dementia Rating Sum of Boxes score. Patients were annually followed up with neuropsychological tests and brain magnetic resonance imaging for 3 years, and underwent a second [11 C] Pittsburgh compound B (PiB) positron emission tomography scan within a mean interval of 32.4 months. There was no difference in the rate of increase in PiB uptake or lacune number between the ES-svMCI and LS-svMCI. However, LS-svMCI showed more rapid cortical thinning and cognitive decline than did the ES-svMCI. We suggest that, whilst the rate of change in pathological burden did not differ between ES-svMCI and LS-svMCI, cortical thinning and cognitive decline progressed more rapidly in the LS-svMCI.

Centiloid method evaluation for amyloid PET of subcortical vascular dementia

Reference region selection is important for proper amyloid PET analysis, especially in subcortical vascular dementia (SVaD) patients. We investigated reference region differences between SVaD and Alzheimer’s disease (AD) using Centiloid scores. In 57 [C-11] Pittsburgh compound B (PiB) positive (+) AD and 23 PiB (+) SVaD patients, we assessed standardized PiB uptake and Centiloid scores in disease-specific cortical regions, with several reference regions: cerebellar gray (CG), whole cerebellum (WC), WC with brainstem (WC + B), pons, and white matter (WM). We calculated disease group differences from young controls (YC) and YC variance according to reference region. SVaD patients showed large effect sizes (Cohen’s d > 0.8) using all reference regions. WM and pons showed larger YC variances than other regions. Findings were similar for AD patients. CG, WC, and WC + B, but not WM or pons, are reliable reference regions for amyloid imaging analysis in SVaD.

Association Between Childhood-Onset Epilepsy and Amyloid Burden 5 Decades Later

The effect of childhood epilepsy on later-life cognitive and brain health is an unclear and little-explored issue. To determine whether adults with a history of childhood-onset epilepsy exhibit increased brain amyloid accumulation, possibly predisposing to accelerated cognitive impairment or even frank cognitive disorders in later life. Forty-one adults from a population-based cohort of individuals with childhood-onset epilepsy in southwestern Finland, together with 46 matched population-based controls, underwent amyloid ligand carbon 11-labeled Pittsburgh Compound B (PiB) positron emission tomography after long-term prospective follow-up. The PiB uptake was quantified as a region to cerebellar cortex ratio. Tracer uptake was evaluated visually and analyzed voxel by voxel over the entire brain to investigate the spatial distribution of amyloid deposition. The study was conducted from May 2011 to October 2013; data analysis was performed from January 2014 to October 2016. Brain amyloid accumulation. The 41 individuals with epilepsy were originally enrolled in the Turku Adult Childhood Onset Epilepsy study at the mean (SD) age of 5.1 (4.5) years (range, 0-14 years). After a mean 52.5 (4.0) years of follow-up, the participants were evaluated (26 [63%] were women; the mean [SD] age was 56.0 [4.3] years). Nine individuals with childhood-onset epilepsy (22%) and 3 control participants (7%) had a visually abnormal PiB scan showing high cortical uptake in at least 1 of the evaluated brain regions (P = .04). In semiquantitative analyses, there was a significant interaction effect indicating higher prefrontal cortex uptake in apolipoprotein E (APOE) ε4 allele carriers than in noncarriers in participants (mean [SD], 1.66 [0.41] vs 1.43 [0.15]) compared with controls (1.40 [0.26) vs 1.41 [0.12]) (group × APOE interaction, F = 6.8; P = .01). In addition, there was a significant group effect showing higher tracer uptake in participants compared with controls (group effect, F = 8.0; P = .006). Adults with childhood-onset epilepsy, particularly APOE ε4 carriers, have an increased brain amyloid load at late middle age. Thus, epilepsy is linked with a biomarker that might be related to accelerated brain aging and can be considered a neurobiological predisposition to later-life cognitive disorders.

Regional amyloid burden and lacune in pure subcortical vascular cognitive impairment

We investigated the amyloid and vascular burden in Pittsburgh compound B (PiB)–negative subcortical vascular mild cognitive impairment (svMCI) and PiB-negative subcortical ischemic vascular dementia (SIVD) to elucidate the potential roles of amyloid deposition and small vessel disease (SVD). Thirty-eight svMCI patients and 42 SIVD patients were enrolled. The regional PiB uptake values and SVD markers were obtained and compared between groups. Additionally, correlations among amyloid burden, SVD, and cognition were made. Patients with PiB-negative SIVD showed more amyloid deposition than those with PiB-negative svMCI, particularly in the cuneus, lingual gyrus, supramarginal, and angular gyri. Despite subthreshold levels for amyloid deposition, our findings showed a marked regional difference in amyloid uptake between svMCI and SIVD, particularly in posteriorly located brain areas. However, lacune, a proxy for vascular burden, showed a broader association with cognition and had more impacts on developing dementia than amyloid burden. The topographical pattern of amyloid deposition and its impact on clinical status in pure subcortical vascular cognitive impairment were different from those in Alzheimer's disease.

AV-1451 tau and β-amyloid positron emission tomography imaging in dementia with Lewy bodies.

ObjectivePatients with probable dementia with Lewy bodies (DLB) often have Alzheimer's disease (AD)‐related pathology. Our objective was to determine the pattern of positron emission tomography (PET) tau tracer AV‐1451 uptake in patients with probable DLB, compared to AD, and its relationship to β‐amyloid deposition on PET.MethodsConsecutive patients with clinically probable DLB (n = 19) from the Mayo Clinic Alzheimer's Disease Research Center underwent magnetic resonance imaging, AV‐1451, and Pittsburgh compound‐B (PiB) PET examinations. Age‐ and sex‐matched groups of AD dementia (n = 19) patients and clinically normal controls (n = 95) from an epidemiological cohort served as a comparison groups. Atlas‐ and voxel‐based analyses were performed.ResultsThe AD dementia group had significantly higher AV‐1451 uptake than the probable DLB group, and medial temporal uptake completely distinguished AD dementia from probable DLB. Patients with probable DLB had greater AV‐1451 uptake in the posterior temporoparietal and occipital cortex compared to clinically normal controls, and in probable DLB, the uptake in these regions correlated with global cortical PiB uptake (Spearman rho = 0.63; p = 0.006).InterpretationMedial temporal lobe AV‐1451 uptake distinguishes AD dementia from probable DLB, which may be useful for differential diagnosis. Elevated posterior temporoparietal and occipital AV‐1451 uptake in probable DLB and its association with global cortical PiB uptake suggest an atypical pattern of tau deposition in DLB. ANN NEUROL 2017;81:58–67

Association of Brain Amyloid-β With Slow Gait in Elderly Individuals Without Dementia

Motor slowing appears in preclinical Alzheimer disease (AD), progresses with AD progression, and is associated with AD pathologic findings at autopsy. Whether amyloid-β (Aβ) is associated with gait speed in elderly individuals without dementia and whether cognition and apolipoprotein E ε4 (APOE ε4) influence this association remain unknown. To examine the association between Aβ and gait speed in elderly individuals without dementia and to study the influence of cognition and APOE ε4 status on this association. This cross-sectional analysis included 183 elderly individuals without dementia, including a cognitively normal (CN) subsample of 144 adults, enrolled in the Ginkgo Evaluation of Memory study at a university center from January 1, 2000, through December 31, 2009, and enrolled in a follow-up substudy a mean (SD) of 10 (3) months after the initial study closeout. Data analysis was performed from October 1, 2015, to June 1, 2016. We assessed cerebral Aβ on Pittsburgh Compound B (PiB) positron emission tomography, gait speed over 4.57 m (15 ft), and cognition on the Mini-Mental State Examination and Trail Making Test Parts A and B. We grouped participants into high Aβ (PiB+) and low Aβ (PiB-) groups on standardized global PiB cutoffs and examined group differences. We studied the influence of cognition and APOE ε4 on the global and regional associations between gait speed and Aβ in the whole sample and the CN subsample. Among the 183 study participants, mean (SD) age was 85.5 (3) years, 76 were women (41.5%), and 177 were white (96.7%). The PiB+ individuals were comparable to the PiB- individuals on demographics, comorbidities, cognition, hippocampal volume, and small-vessel disease but not on gait speed (0.85 vs 0.92 m/s, P = .01) or proportion of APOE ε4 carriers (29 [29.0%] vs 5 [6.0%], P < .001). In the whole sample and the CN subsample, the association between global PiB retention and slower gait withstood adjustment for covariates (β = -0.068, P = .03 and β = -0.074, P = .04, respectively); however, this association was attenuated by Mini-Mental State Examination and Trail Making Test Parts A and B and was rendered statistically nonsignificant by APOE ε4 in both samples (β = -0.055 and β = -0.058, respectively; both P ≥ .10). Several regional associations between gait speed and PiB uptake withstood relevant adjustments; however, APOE ε4 rendered only the medial (β = -0.22, P = .03) and lateral (β = -0.08, P = .03) temporal regions, subcortical white matter (β = -0.13, P = .02), and occipital regions (β = -0.15, P = .03) in the whole sample and the occipital regions (β = -0.21, P = .01) in the CN subsample statistically significant. Cerebral Aβ deposition is associated with slower gait speed in elderly individuals without dementia; however, this association is weaker in those who are CN. Cognition and APOE ε4 carrier status influence the association between Aβ and gait speed in elderly individuals without dementia.

Synergistic effects of longitudinal amyloid and vascular changes on lobar microbleeds

To determine whether amyloid and hypertensive cerebral small vessel disease (hCSVD) changes synergistically affect the progression of lobar microbleeds in patients with subcortical vascular mild cognitive impairment (svMCI). Among 72 patients with svMCI who underwent brain MRI and [11C] Pittsburgh compound B (PiB)-PET, 52 (72.2%) completed the third year of follow-up. These patients were evaluated by annual neuropsychological testing, brain MRI, and follow-up PiB-PET. Over 3 years, 31 of 52 patients (59.6%) had incident cerebral microbleeds (CMBs) in the lobar and deep regions. Both baseline and longitudinal changes in lacune numbers were associated with increased numbers of lobar and deep microbleeds, while baseline and longitudinal changes in PiB uptake ratio were associated only with the progression of lobar microbleeds, especially in the temporal, parietal, and occipital areas. Regional white matter hyperintensity severity was also associated with regional lobar CMBs in the parietal and occipital regions. There were interactive effects between baseline and longitudinal lacune number and PiB retention on lobar microbleed progression. Increased lobar, but not deep, CMBs were associated with decreased scores in the digit span backward task and Rey-Osterrieth Complex Figure Test. Our findings suggest that amyloid-related pathology and hCSVD have synergistic effects on the progression of lobar microbleeds, providing new clinical insight into the interaction between amyloid burden and hCSVD on CMB progression and cognitive decline with implications for developing effective prevention strategies.

CSF proteins and resting-state functional connectivity in Parkinson disease.

The purpose of this study was to investigate the relationship between disruption of MRI-measured resting-state functional connectivity (rs-fcMRI) brain networks and CSF levels of potentially pathogenic proteins that reflect brain pathology in Parkinson disease (PD). PD participants without dementia (n = 43) and age-matched controls (n = 22) had lumbar punctures to measure CSF protein levels, Pittsburgh compound B (PiB)-PET imaging, and rs-fcMRI while off medication. Imaging analyses focused on 5 major resting-state networks as well as the striatum. Participants with PD had significantly reduced sensorimotor functional connectivity, which correlated with reduced CSF levels of α-synuclein. The PD group also had significantly stronger default mode network functional connectivity that did not correlate with CSF β-amyloid (Aβ)42 or PiB uptake. In contrast, default mode network functional connectivity in the control group did correlate with CSF Aβ42 levels. Functional connectivity was similar between groups in the dorsal attention, control, and salience networks. These results suggest that abnormal α-synuclein accumulation, but not Aβ, contributes to the disruption of motor-related functional connectivity in PD. Furthermore, correlating CSF protein measures with the strength of resting-state networks provides a direct link between abnormal α-synuclein metabolism and disrupted brain function in PD.