11C-PiB Positron Emission Tomography Research Articles

Differential centiloid scale normalization techniques: comparison between hybrid PET/MRI and independently acquired MRI.

Centiloid (CL) scales play an important role in semiquantitative analyses of amyloid-β (Aβ) PET. CLs are derived from the standardized uptake value ratio (SUVR), which needs Aβ positron emission tomography (PET) normalization processing. There are two methods to collect the T1-weighted imaging (T1WI) for normalization: (i) anatomical standardization using simultaneously acquired T1WI (PET/MRI), usually adapted to PET images from PET/MRI scanners, and (ii) T1WI from a separate examination (PET + MRI), usually adapted to PET images from PET/CT scanners. This study aimed to elucidate the correlations and differences in CLs between when using the above two T1WI collection methods. Among patients who underwent Aβ PET/MRI (using 11C-Pittuberg compound B (11C-PiB) or 18F-flutemetamol (18F-FMM)) at our institution from 2015 to 2023, we selected 49 patients who also underwent other additional MRI examinations, including T1WI for anatomic standardization within 3years. Thirty-one of them underwent 11C-PiB PET/MRI, and 18 participants underwent 18F-FMM PET/MRI. Twenty-five of them, additional MRI acquisition parameters were identical to simultaneous MRI during PET, and 24 participants were different.After normalization using PET/MRI or PET + MRI method each, SUVR was measured using the Global Alzheimer's Association Initiative Network cerebral cortical and striatum Volume of Interest templates (VOI) and whole cerebellum VOI. Subsequently, CLs were calculated using the previously established equations for each Aβ PET tracer. Between PET/MRI and PET + MRI methods, CLs correlated linearly in 11C-PiB PET (y = 1.00x - 0.11, R2 = 0.999), 18F-FMM PET (y = 0.97x - 0.12, 0.997), identical additional MRI acquisition (y = 1.00x + 0.33, 0.999), different acquisition (y = 0.98x - 0.43, 0.997), and entire study group (y = 1.00x - 0.24, 0.999). Wilcoxon signed-rank test revealed no significant differences: 11C-PiB (p = 0.49), 18F-FMM (0.08), and whole PET (0.46). However, significant differences were identified in identical acquisition (p = 0.04) and different acquisition (p = 0.02). Bland-Altman analysis documented only a small bias between PET/MRI and PET + MRI in 11C-PiB PET, 18F-FMM PET, identical additional MRI acquisition, different acquisition, and whole PET (-0.05, 0.67, -0.30, 0.78, and 0.21, respectively). Anatomical standardizations using PET/MRI and using PET + MRI can lead to almost equivalent CL. The CL values obtained using PET/MRI or PET + MRI normalization methods are consistent and comparable in clinical studies.

P101 Brain Amyloid Burden and Autobiographical Memory in Obstructive Sleep Apnoea: A Cross-sectional Study.

Abstract Introduction Emerging literature reports an increased risk of Alzheimer’s disease in individuals with obstructive sleep apnoea (OSA). Established characteristics of Alzheimer’s disease include increased brain amyloid burden and impairment to episodic and autobiographical memory. Investigating these constructs in individuals with clinically confirmed OSA will contribute to understanding of OSA and neuronal implications. Aim The aim of the study was to explore the relationship between brain amyloid burden and autobiographical memory in cognitively-healthy individuals with OSA. Methods Thirty-four participants with OSA (mean age=57.7, SD=8.5, 19 males), and 12 controls (mean age=57.1, SD=8.1, 6 males) participated in the study. Participants underwent a 11C-PiB positron emission tomography (PET) scan to quantify amyloid burden, and an assessment of autobiographical memory. Brain amyloid burden was quantified using the standardised uptake value ratio (SUVR), and the Autobiographical Memory Test (AMT) was used to assess the ability of participants to recall specific memories from their life. Results Individuals with OSA recalled significantly fewer specific autobiographical memories (M=6.66, SD=2.91) compared to controls (M=10.25, SD=2.09, t(45)=-3.930, p<.001). There was no significant difference in SUVR between groups, t(44)=1.465, p=.150. Recall of non-specific memories was significantly positively correlated with SUVR, r=.331, p=.026. Discussion Levels of brain amyloid burden did not differ significantly between groups however the results support existing literature suggesting amyloid burden is associated with autobiographical memory in individuals with OSA. Longitudinal studies investigating the trajectory of these constructs in the context of disease development should be conducted to further explore the impacts of OSA.

Head-to-head comparison of plasma p-tau181, p-tau231 and glial fibrillary acidic protein in clinically unimpaired elderly with three levels of APOE4-related risk for Alzheimer's disease

Plasma phosphorylated tau (p-tau) and glial fibrillary acidic protein (GFAP) both reflect early changes in Alzheimer's disease (AD) pathology. Here, we compared the biomarker levels and their association with regional β-amyloid (Aβ) pathology and cognitive performance head-to-head in clinically unimpaired elderly (n = 88) at three levels of APOE4-related genetic risk for sporadic AD (APOE4/4 n = 19, APOE3/4 n = 32 or non-carriers n = 37). Concentrations of plasma p-tau181, p-tau231 and GFAP were measured using Single molecule array (Simoa), regional Aβ deposition with 11C-PiB positron emission tomography (PET), and cognitive performance with a preclinical composite. Significant differences in plasma p-tau181 and p-tau231, but not plasma GFAP concentrations were present between the APOE4 gene doses, explained solely by brain Aβ load. All plasma biomarkers correlated positively with Aβ PET in the total study population. This correlation was driven by APOE3/3 carriers for plasma p-tau markers and APOE4/4 carriers for plasma GFAP. Voxel-wise associations with amyloid-PET revealed different spatial patterns for plasma p-tau markers and plasma GFAP. Only higher plasma GFAP correlated with lower cognitive scores. Our observations suggest that plasma p-tau and plasma GFAP are both early AD markers reflecting different Aβ-related processes.

APOE ε4 gene dose effect on imaging and blood biomarkers of neuroinflammation and beta-amyloid in cognitively unimpaired elderly

BackgroundNeuroinflammation, characterized by increased reactivity of microglia and astrocytes in the brain, is known to be present at various stages of the Alzheimer’s disease (AD) continuum. However, its presence and relationship with amyloid pathology in cognitively normal at-risk individuals is less clear. Here, we used positron emission tomography (PET) and blood biomarker measurements to examine differences in neuroinflammation and beta-amyloid (Aβ) and their association in cognitively unimpaired homozygotes, heterozygotes, or non-carriers of the APOE ε4 allele, the strongest genetic risk for sporadic AD.MethodsSixty 60–75-year-old APOE ε4 homozygotes (n = 19), heterozygotes (n = 21), and non-carriers (n = 20) were recruited in collaboration with the local Auria biobank. The participants underwent 11C-PK11195 PET (targeting 18-kDa translocator protein, TSPO), 11C-PiB PET (targeting Aβ), brain MRI, and neuropsychological testing including a preclinical cognitive composite (APCC). 11C-PK11195 distribution volume ratios and 11C-PiB standardized uptake value ratios (SUVRs) were calculated for regions typical for early Aβ accumulation in AD. Blood samples were drawn for measuring plasma glial fibrillary acidic protein (GFAP) and plasma Aβ1-42/1.40.ResultsIn our cognitively unimpaired sample, cortical 11C-PiB-binding increased according to APOE ε4 gene dose (median composite SUVR 1.47 (range 1.38–1.66) in non-carriers, 1.55 (1.43–2.02) in heterozygotes, and 2.13 (1.61–2.83) in homozygotes, P = 0.002). In contrast, cortical composite 11C-PK11195-binding did not differ between the APOE ε4 gene doses (P = 0.27) or between Aβ-positive and Aβ-negative individuals (P = 0.81) and associated with higher Aβ burden only in APOE ε4 homozygotes (Rho = 0.47, P = 0.043). Plasma GFAP concentration correlated with cortical 11C-PiB (Rho = 0.35, P = 0.040), but not 11C-PK11195-binding (Rho = 0.13, P = 0.47) in Aβ-positive individuals. In the total cognitively unimpaired population, both higher composite 11C-PK11195-binding and plasma GFAP were associated with lower hippocampal volume, whereas elevated 11C-PiB-binding was associated with lower APCC scores.ConclusionsOnly Aβ burden measured by PET, but not markers of neuroinflammation, differed among cognitively unimpaired elderly with different APOE ε4 gene dose. However, APOE ε4 gene dose seemed to modulate the association between neuroinflammation and Aβ.

Evaluation of 10-minute post-injection 11C-PiB PET and its correlation with 18F-FDG PET in older adults who are cognitively healthy, mildly impaired, or with probable Alzheimer's disease.

Objective:Positron emission tomography (PET) allows in vivo evaluation of molecular targets in neurodegenerative diseases, such as Alzheimer’s disease. Mild cognitive impairment is an intermediate stage between normal cognition and Alzheimer-type dementia. In vivo fibrillar amyloid-beta can be detected in PET using [11C]-labeled Pittsburgh compound B (11C-PiB). In contrast, [18F]fluoro-2-deoxy-d-glucose (18F-FDG) is a neurodegeneration biomarker used to evaluate cerebral glucose metabolism, indicating neuronal injury and synaptic dysfunction. In addition, early cerebral uptake of amyloid-PET tracers can determine regional cerebral blood flow. The present study compared early-phase 11C-PiB and 18F-FDG in older adults without cognitive impairment, amnestic mild cognitive impairment, and clinical diagnosis of probable Alzheimer’s disease.Methods:We selected 90 older adults, clinically classified as healthy controls, with amnestic mild cognitive impairment, or with probable Alzheimer’s disease, who underwent an 18F-FDG PET, early-phase 11C-PiB PET and magnetic resonance imaging. All participants were also classified as amyloid-positive or -negative in late-phase 11C-PiB. The data were analyzed using statistical parametric mapping.Results:We found that the probable Alzheimer’s disease and amnestic mild cognitive impairment group had lower early-phase 11C-PiB uptake in limbic structures than 18F-FDG uptake. The images showed significant interactions between amyloid-beta status (negative or positive). However, early-phase 11C-PiB appears to provide different information from 18F-FDG about neurodegeneration.Conclusions:Our study suggests that early-phase 11C-PiB uptake correlates with 18F-FDG, irrespective of the particular amyloid-beta status. In addition, we observed distinct regional distribution patterns between both biomarkers, reinforcing the need for more robust studies to investigate the real clinical value of early-phase amyloid-PET imaging.

Myelin imaging measures as predictors of cognitive impairment in MS patients: A hybrid PET-MRI study

BackgroundCognitive impairment is one of the concerns of Multiple Sclerosis (MS) and has been related to myelin loss. Different neuroimaging methods have been used to quantify myelin and relate it to cognitive dysfunctions, among them Magnetization Transfer Ratio (MTR), Diffusion Tensor Imaging (DTI), and, more recently, Positron Emission Tomography (PET) with 11C-PIB. ObjectiveTo investigate different myelin imaging modalities as predictors of cognitive dysfunction. MethodsFifty-one MS patients and 24 healthy controls underwent clinical and neuropsychological assessment and MTR, DTI (Axial Diffusion-AD and Fractional Anisotropy-FA maps), and 11C-PIB PET images in a PET/MR hybrid system. ResultsMTR and DTI(FA) differed in patients with or without cognitive impairment. There was an association of DTI(FA) and DTI(AD) with cognition and psychomotor speed for progressive MS, and of 11C-PIB uptake and MTR for relapsing-remitting MS. MTR in the Thalamus (β= -0.51, p = 0.021) and Corpus Callosum (β= -0.24, p = 0.033) were predictive of cognitive impairment. DTI-FA in the Caudate (β= -26.93, p = 0.006) presented abnormal predictive result. ConclusionLower myelin content by 11C-PIB uptake was associated with worse cognitive status. MTR was predictive of cognitive impairment in MS.

Improving contrast between gray and white matter of Logan graphical analysis’ parametric images in positron emission tomography through least-squares cubic regression and principal component analysis

Logan graphical analysis (LGA) is a method for in vivo quantification of tracer kinetics in positron emission tomography (PET). The shortcoming of LGA is the presence of a negative bias in the estimated parameters for noisy data. Various approaches have been proposed to address this issue. We recently applied an alternative regression method called least-squares cubic (LSC), which considers the errors in both the predictor and response variables to estimate the LGA slope. LSC reduced the bias in non-displaceable binding potential estimates while causing slight increases in the variance. In this study, we combined LSC with a principal component analysis (PCA) denoising technique to counteract the effects of variance on parametric image quality, which was assessed in terms of the contrast between gray and white matter. Tissue time–activity curves were denoised through PCA, prior to estimating the regression parameters using LSC. We refer to this approach as LSC–PCA. LSC–PCA was assessed against OLS–PCA (PCA with ordinary least-squares (OLS)), LSC, and conventional OLS-based LGA. Comparisons were made for simulated 11 C-carfentanil and 11C Pittsburgh compound B (11C-PiB) data, and clinical 11 C-PiB PET images. PCA-based methods were compared over a range of principal components, varied by the percentage variance they account for in the data. The results showed reduced variances in distribution volume ratio estimates in the simulations for LSC–PCA compared to LSC, and lower bias compared to OLS–PCA and OLS. Contrasts were not significantly improved in clinical data, but they showed a significant improvement in simulation data —indicating a potential advantage of LSC–PCA over OLS–PCA. The effects of bias reintroduction when many principal components are used were also observed in OLS–PCA clinical images. We therefore encourage the use of LSC–PCA. LSC–PCA can allow the use of many principal components with minimal risk of bias, thereby strengthening the interpretation of PET parametric images.

Positron Emission Tomography Imaging for In Vivo Measuring of Myelin Content in the Lysolecithin Rat Model of Multiple Sclerosis.

Multiple sclerosis (MS) is a neuroinflammatory disease with expanding axonal and neuronal degeneration and demyelination in the central nervous system, leading to motor dysfunctions, psychical disability, and cognitive impairment during MS progression. Positron emission tomography (PET) is an imaging technique able to quantify in vivo cellular and molecular alterations. Radiotracers with affinity to intact myelin can be used for in vivo imaging of myelin content changes over time. It is possible to detect either an increase or decrease in myelin content, what means this imaging technique can detect demyelination and remyelination processes of the central nervous system. In this protocol we demonstrate how to use PET imaging to detect myelin changes in the lysolecithin rat model, which is a model of focal demyelination lesion (induced by stereotactic injection) (i.e., a model of multiple sclerosis disease). 11C-PIB PET imaging was performed at baseline, and 1 week and 4 weeks after stereotaxic injection of lysolecithin 1% in the right striatum (4 µL) and corpus callosum (3 µL) of the rat brain, allowing quantification of focal demyelination (injection site after 1 week) and the remyelination process (injection site at 4 weeks). Myelin PET imaging is an interesting tool for monitoring in vivo changes in myelin content which could be useful for monitoring demyelinating disease progression and therapeutic response.

Severe Obstructive Sleep Apnea Is Associated with Higher Brain Amyloid Burden: A Preliminary PET Imaging Study.

Obstructive sleep apnea (OSA) has been linked to an increase risk of dementia. Few studies have cross-sectionally examined whether clinically-confirmed OSA is associated with a higher brain amyloid burden. The aim of this study was to compare brain amyloid burden in individuals with untreated OSA and healthy controls, and explore associations between amyloid burden and polysomnographic and subjective measures of sleep, demographics, and mood. Thirty-four individuals with OSA (mean age 57.5±4.1 y; 19 males) and 12 controls (mean age 58.5±4.2 y; 6 males) underwent a clinical polysomnogram and a 11C-PiB positron emission tomography (PET) scan to quantify amyloid burden. Amyloid burden was elevated in the OSA group relative to controls, and was significantly higher in those with severe OSA relative to mild/moderate OSA. Correlation analyses indicated that higher amyloid burden was associated with a higher Non-REM apnea hypopnea index, poorer sleep efficiency, and less time spent in stage N3 sleep, when controlling for age. Severe OSA is associated with a modest elevation of brain amyloid, the significance of which should be further investigated to explore the implications for dementia risk.

Non-invasive detection and differentiation of cardiac amyloidosis using 99mTc-pyrophosphate scintigraphy and 11C-Pittsburgh compound B PET imaging

Purpose To investigate the utility of the combined use of 11C-Pittsburgh compound B (11C-PiB) positron emission tomography (PET) imaging and 99mTc-pyrophosphate (99mTc-PYP) scintigraphy for detection and differentiation of three major types of cardiac amyloidosis, i.e. immunoglobulin light chain (AL), hereditary transthyretin (ATTRv), and wild-type transthyretin (ATTRwt) amyloidosis. Methods Whole-body 11C-PiB PET and 99mTc-PYP scintigraphy were performed in 17 patients with AL amyloidosis, 22 patients with ATTRv, and eight patients with ATTRwt amyloidosis. The correlations between organ involvement and the uptake of 11C-PiB and 99mTc-PYP were analyzed in each patient. Results Cardiac amyloidosis was detectable by 99mTc-PYP scintigraphy or 11C-PiB PET in all systemic amyloidosis patients with cardiac involvement. 99mTc-PYP scintigraphy and 11C-PiB PET showed an interesting complementary relation. Strict combination of positive 11C-PiB and negative 99mTc-PYP uptake (PiB pattern) was observed in all AL amyloidosis patients with cardiac involvement. In contrast, strict combination of positive 99mTc-PYP and negative 11C-PiB uptake (PYP pattern) was observed in all ATTRwt amyloidosis patients with cardiac involvement. ATTRv amyloidosis patients with cardiac involvement were divided into two groups: PiB pattern or PYP pattern. All of the early-onset V30M (p.V50M) ATTRv patients showed the PiB pattern, whereas all of the late-onset V30M and non-V30M ATTRv patients showed the PYP pattern. Conclusions All three major types of cardiac amyloidosis can be detected and differentiated non-invasively by combined use of the two amyloid imaging methods and TTR gene testing.

The relationships between neuroinflammation, beta-amyloid and tau deposition in Alzheimer\u2019s disease: a longitudinal PET study

BackgroundThe aim of this longitudinal study was to assess with positron emission tomography (PET) the relationship between levels of inflammation and the loads of aggregated β-amyloid and tau at baseline and again after 2 years in prodromal Alzheimer's disease.MethodsForty-three subjects with mild cognitive impairment (MCI) had serial 11C-PK11195 PET over 2 years to measure inflammation changes, and 11C-PiB PET to determine β-amyloid fibril load; 22 also had serial 18F-Flortaucipir PET to determine tau tangle load. Cortical surface statistical mapping was used to localise areas showing significant changes in tracer binding over time and to interrogate correlations between tracer binding of the tracers at baseline and after 2 years.ResultsThose MCI subjects with high 11C-PiB uptake at baseline (classified as prodromal Alzheimer’s disease) had raised inflammation levels which significantly declined across cortical regions over 2 years although their β-amyloid levels continued to rise. Those MCI cases who had low/normal 11C-PiB uptake at baseline but their levels then rose over 2 years were classified as prodromal AD with low Thal phase 1-2 amyloid deposition at baseline. They showed levels of cortical inflammation which correlated with their rising β-amyloid load. Those MCI cases with baseline low 11C-PiB uptake that remained stable were classified as non-AD, and they showed no correlated inflammation levels. Finally, MCI cases which showed both high 11C-PiB and 18F-Flortaucipir uptake at baseline (MCI due to AD) showed a further rise in their tau tangle load over 2 years with a correlated rise in levels of inflammation.ConclusionsOur baseline and 2-year imaging findings are compatible with a biphasic trajectory of inflammation in Alzheimer’s disease: MCI cases with low baseline but subsequently rising β-amyloid load show correlated levels of microglial activation which then later decline when the β-amyloid load approaches AD levels. Later, as tau tangles form in β-amyloid positive MCI cases with prodromal AD, the rising tau load is associated with higher levels of inflammation.

The correlation of neuropsychological evaluation with 11C-PiB and 18F-FC119S amyloid PET in mild cognitive impairment and Alzheimer disease.

For the diagnosis of mild cognitive impairment (MCI) and Alzheimer disease (AD), variable neuroimaging and neuropsychological tests have been used. We aimed to evaluate the correlation of neuropsychological domain with new amyloid positron emission tomography (PET) study and to validate the availability of new PET tracer.We enrolled 20 patients who underwent 11C-PiB-PET/CT, new PET tracer 18F-FC119S PET/CT from November, 2014 to July, 2015. Among them, 10 patients were diagnosed with AD and 10 patients with MCI. The current version of Seoul Neuropsychological Screening Battery (SNSB) II was performed for cognitive evaluation. Each parameter of SNSB was compared between 2 patient groups. Spearman correlation analysis between value of SNSB domain and standardized uptake value ratio (SUVR) of PET was also performed.The AD group presented significant poor z-score in Korean-Boston Naming Test(K-BNT) (P = .01),copy score of Rey Complex Figure Test (RCFT) (P = .049), immediate (P = .028)and delayed memory of Seoul Verbal Learning Test (SVLT) (P = .028), recognition of RCFT (P = .004), “animal” of Controlled Oral Word Association Test (COWAT) (P = .041), color reading of Korean-Color Word Stroop test (K-CWST) (P = .014), and Digit Symbol Coding (DSC) (P = .007) compared with MCI group. That means, except attention domain, all other cognitive domains were relatively impaired in AD compared with MCI. In correlation analysis, we found that poor performances on copy score of RCFT in MCI groups were associated with great beta amyloid burden in frontal area in both 11C-PiB-PET/CT and 18F-FC119S PET/CT. In AD group, 18F-FC119S PET presented more extensive correlation in each cognitive domain with multiple cortical areas compared with 11C-PiB-PET.The degree of amyloid burden assessed on 18F-FC119S PET was significantly correlated with neuropsychological test in AD, and also MCI patients. The combination of neuropsychological evaluation with novel 18F-FC119S PET/CT can be used for valid biomarker for MCI and AD.

Personalized Computer-Aided Diagnosis for Mild Cognitive Impairment in Alzheimer’s Disease Based on sMRI and ¹¹C PiB-PET Analysis

Alzheimer’s disease (AD) is a neurodegenerative condition that affects the central nervous system and represents 60% to 70% of all dementia cases. Due to an increased aging population, the number of patients diagnosed with AD is expected to exceed 131 million worldwide by 2050. The disease is characterized by various clinical symptoms and pathological features that define three main sequential decline stages, namely, early/mild, intermediate/moderate and late/severe stages. Although it is considered irreversible, early diagnosis of AD is highly desirable to help preserve cognitive function. However, early diagnosis is difficult due to different factors, including the patient-specific development of AD. The main contribution of the proposed work is to present a personalized (i.e., local/brain regional) computer-aided diagnosis (CAD) system for early diagnosis of AD from two perspectives, functional and structural to assist diagnosis. In other words, the proposed system uniquely yields local/regional diagnosis by combining 11C PiB positron emission tomography (11C PiB PET), which provides functional diagnosis, with structural magnetic resonance imaging (sMRI), which provides structural diagnosis. To the best of our knowledge, this is the first work to combine sMRI and the 11C PiB PET for local/regional early diagnosis of AD. The system processes the two modalities through a number of steps: pre-processing, brain labeling (parcellation), feature extraction, and diagnosis. A local/regional diagnosis is presented for each modality separately, followed by the final global diagnosis obtained by integrating the results from the two modalities. Evaluation of the proposed system shows average results of 97.5%, 100%, and 96.77% for accuracy, specificity, and sensitivity, respectively. With further development, it is envisioned that this system could contribute to the early diagnosis of AD in the clinical setting.

Association between neurite metrics and tau/inflammatory pathology in Alzheimer's disease.

IntroductionThe molecular mechanism of neurodegeneration, including tau and neurite complexity, is an important topic in Alzheimer's disease (AD) research.MethodsWe recruited 27 amyloid‐positive individuals identified through 11C‐Pittsburgh compound B (PiB) positron emission tomography (PET) and 31 amyloid‐negative individuals with normal cognition. All participants underwent 11C‐PiB and 18F‐THK5351 PET and magnetic resonance imaging (MRI) with neurite orientation dispersion and density imaging (NODDI) protocol. The neurite density index (NDI), orientation dispersion index (ODI), and PET images were analyzed to calculate voxel‐wise correlations among the imaging modalities and correlations with cognitions.ResultsIn the amyloid‐positive participants, there were significant negative correlations between 18F‐THK5351 and NDI and between 18F‐THK5351 and ODI. The bilateral mesial and lateral temporal lobes were mainly involved. Regarding cognition, 18F‐THK5351 showed more marked associations with all cognitive domains than the other modalities.DiscussionTau and neuroinflammation in AD may reduce the neurite density and orientation dispersion, particularly in the mesial and lateral temporal lobes.

Increased cerebral blood flow with increased amyloid burden in the preclinical phase of alzheimer's disease.

Arterial spin labeling (ASL) is an emerging MRI technique for noninvasive measurement of cerebral blood flow (CBF) that has been used to show hemodynamic changes in the brains of people with Alzheimer's disease (AD). CBF changes have been measured using positron emission tomography (PET) across the AD spectrum, but ASL showed limited success in measuring CBF variations in the preclinical phase of AD, where amyloid β (Aβ) plaques accumulate in the decades prior to symptom onset. To investigate the relationship between CBF measured by multiphase-pseudocontinuous-ASL (MP-PCASL) and Aβ burden as measured by 11 C-PiB PET imaging in a study of cognitively normal (CN) subjects age over 65. Cross-sectional. Forty-six CN subjects including 33 with low levels of Aβ burden and 13 with high levels of Aβ. 3T/3D MP-PCASL. The MP-PCASL method was chosen because it has a high signal-to-noise ratio. Furthermore, the data were analyzed using an efficient processing pipeline consisting of motion correction, ASL motion correction imprecision removal, temporal and spatial filtering, and partial volume effect correction. General Linear Model. In CN subjects positive for Aβ burden (n = 13), we observed a positive correlation between CBF and Aβ burden in the hippocampus, amygdala, caudate (P < 0.01), frontal, temporal, and insula (P < 0.05). To the best of our knowledge, this is the first study using MP-PCASL in the study of AD, and the results suggest a potential compensatory hemodynamic mechanism that protects against pathology in the early stages of AD. 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2020;51:505-513.

Abnormal Amyloid Load in Mild Cognitive Impairment: The Effect of Reducing the PiB-PET Threshold.

In vivo detection of β-amyloid (Aβ) plaques in Alzheimer's disease (AD) is now possible with 11 C-PiB positron emission tomography (PET). Conventionally, a cortical:cerebellar PiB uptake ratio threshold of 1.4-1.5 has been used to categorize at-risk subjects as "amyloid-positive" and "amyloid-negative." It has been suggested that this threshold is too conservative and may miss early amyloid pathology. We investigated the relationship between conventional and lower baseline 11 C-PiB PET thresholds for raised amyloid load and the subsequent clinical and radiological progression of mild cognitive impairment (MCI) cases longitudinally. We serially determined the cortical amyloid load with 11 C-PiB PET of 44 MCI subjects over 2 years and compared findings with those for 12 healthy controls (HC) and 5 AD cases. Twenty-four subjects were classified as normal at baseline with mean cortical PiB standard uptake value ratios (SUVR) between 1.2 and 1.5. Their cognitive status remained stable over time. Three of these cases increased their amyloid load above a threshold of 1.5 over 2 years. Twenty-seven "raised amyloid" MCI cases with baseline cortical SUVRs above 1.5, showed deteriorating cognition. Note that 50% of these cases converted clinically to AD during the follow-up period. Use of a PiB SUVR threshold of >1.5 for raised amyloid missed 14.3% of MCI cases who likely had Thal stage 1 or 2 pathology and showed a progressive amyloid increase over 2 years. Lowering the threshold for abnormality to 1.3 abolished all false negatives but resulted in 75% of HCs being falsely diagnosed as raised amyloid subjects.

Topography of 11C-Pittsburgh compound B uptake in Alzheimer's disease: a voxel-based investigation of cortical and white matter regions.

Objective:To compare results of positron emission tomography (PET) with carbon-11-labeled Pittsburgh compound B (11C-PIB) obtained with cerebellar or global brain uptake for voxel intensity normalization, describe the cortical sites with highest tracer uptake in subjects with mild Alzheimer’s disease (AD), and explore possible group differences in 11C-PIB binding to white matter.Methods: 11C-PIB PET scans were acquired from subjects with AD (n=17) and healthy elderly controls (n=19). Voxel-based analysis was performed with statistical parametric mapping (SPM).Results:Cerebellar normalization showed higher 11C-PIB uptake in the AD group relative to controls throughout the cerebral cortex, involving the lateral temporal, orbitofrontal, and superior parietal cortices. With global uptake normalization, greatest cortical binding was detected in the orbitofrontal cortex; decreased 11C-PIB uptake in white matter was found in the posterior hippocampal region, corpus callosum, pons, and internal capsule.Conclusion:The present case-control voxelwise 11C-PIB PET comparison highlighted the regional distribution of amyloid deposition in the cerebral cortex of mildly demented AD patients. Tracer uptake was highest in the orbitofrontal cortex. Decreased 11C-PIB uptake in white-matter regions in this patient population may be a marker of white-matter damage in AD.

Visual cognition in non-amnestic Alzheimer's disease: Relations to tau, amyloid, and cortical atrophy.

Heterogeneity within the Alzheimer's disease (AD) syndromic spectrum is typically classified in a domain-specific manner (e.g., language vs. visual cognitive function). The central aim of this study was to investigate whether impairment in visual cognitive tasks thought to be subserved by posterior cortical dysfunction in non-amnestic AD presentations is associated with tau, amyloid, or neurodegeneration in those regions using 18F-AV-1451 and 11C-PiB positron emission tomography (PET) and magnetic resonance imaging (MRI). Sixteen amyloid-positive patients who met criteria for either Posterior Cortical Atrophy (PCA; n = 10) or logopenic variant Primary Progressive Aphasia (lvPPA; n = 6) were studied. All participants underwent a structured clinical assessment, neuropsychological battery, structural MRI, amyloid PET, and tau PET. The neuropsychological battery included two visual cognitive tests: VOSP Number Location and Benton Facial Recognition. Surface-based whole-cortical general linear models were used to first explore the similarities and differences between these biomarkers in the two patient groups, and then to assess their regional associations with visual cognitive test performance. The results show that these two variants of AD have both dissociable and overlapping areas of tau and atrophy, but amyloid is distributed with a stereotyped localization in both variants. Performance on both visual cognitive tests were associated with tau and atrophy in the right lateral and medial occipital association cortex, superior parietal cortex, and posterior ventral occipitotemporal cortex. No cortical associations were observed with amyloid PET. We further demonstrate that cortical atrophy has a partially mediating effect on the association between tau pathology and visual cognitive task performance. Our findings show that non-amnestic variants of AD have partially dissociable spatial patterns of tau and atrophy that localize as expected based on symptoms, but similar patterns of amyloid. Further, we demonstrate that impairments of visual cognitive dysfunction are strongly associated with tau in visual cortical regions and mediated in part by atrophy.

Visualization of multiple organ amyloid involvement in systemic amyloidosis using 11C-PiB PET imaging.

To investigate the utility of Pittsburgh compound B (PiB) positron emission tomography (PET) imaging for evaluating whole-body amyloid involvement in patients with systemic amyloidosis. Whole-body 11C-PiB PET was performed in seven patients with systemic immunoglobulin light-chain (AL) amyloidosis, seven patients with hereditary transthyretin (ATTRm) amyloidosis, one asymptomatic TTR mutation carrier and three healthy controls. The correlations between clinical organ involvement, radiological 11C-PiB uptake and histopathological findings were analysed for each organ. Organ involvement on 11C-PiB PET imaging showed good correlations with the clinical findings for the heart and stomach. Abnormal tracer uptake was also observed in the spleen, lachrymal gland, submandibular gland, sublingual gland, lymph node, brain, scalp, extraocular muscles, nasal mucosa, pharynx, tongue and nuchal muscles, most of which were asymptomatic. Physiological tracer uptake was universally observed in the urinary tract (kidney, renal pelvis, ureter and bladder) and enterohepatic circulatory system (liver, gallbladder, bile duct and small intestine) in all participants. Most of the patients and one healthy control subject showed asymptomatic tracer uptake in the lung and parotid gland. The peripheral nervous system did not show any tracer uptake even in patients with apparent peripheral neuropathy. Histological amyloid deposition was confirmed in biopsied myocardium and gastric mucosa where abnormal 11C-PiB retention was observed. 11C-PiB PET imaging can be used clinically in the systemic evaluation of amyloid distribution in patients with AL and ATTRm amyloidosis. Quantitative analysis of 11C-PiB PET images may be useful in therapy evaluation and will reveal whether amyloid clearance is correlated with clinical response.

Inotropic myocardial reserve deficiency is the predominant feature of exercise haemodynamics in cardiac amyloidosis.

This study aimed to characterize invasive haemodynamics during exercise in subjects with cardiac amyloidosis (CA). The study population numbered 44 subjects. Group A (CA-positive, n = 24) comprised wild-type transthyretin patients (n = 10), familial transthyretin amyloidosis mutation carriers (ATTRm) with cardiac involvement (n = 5), and light-chain amyloidosis patients with cardiac involvement (n = 9). Group B (CA-negative, n = 20) comprised four healthy ATTRm subjects without cardiac involvement documented by 11 C-PIB positron emission tomography and 16 healthy controls. All subjects underwent a symptom-limited, semi-supine exercise test with expired gas analysis and simultaneous right heart catheterization. CA patients had lower peak oxygen consumption [15 ± 6 mL/min/kg bodyweight (bwt) vs. 33 ± 7 mL/min/kg bwt; P < 0.0001] than controls. Myocardial reserve during exercise was significantly reduced in CA patients as reflected in a small increase in stroke volume index (SVI) and cardiac index (CI) compared with controls [ΔSVI: 4 mL/m2 (range: -1 to 8) vs. 14 mL/m2 (range: 5-25); P < 0.0001; ΔCI: 2 ± 2 L/min vs. 7 ± 2 L/min; P < 0.0001]. During exercise, CA patients had significantly higher left and right ventricular filling pressures than controls. Furthermore, CA patients had severely impaired pulmonary arterial compliance (PAC) compared with controls [2.9 mL/mmHg (range: 2.1-4.5) vs. 7.5 mL/mmHg (range: 5.7-10.4); P < 0.0001]. Cardiac amyloid deposits are associated with severely reduced inotropic myocardial reserve and increased left and right ventricular filling pressures during exercise. Furthermore, CA subjects have severely reduced PAC, which may contribute to right heart failure and reduced exercise capacity.