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

The widespread deposition of amyloid-ß (Aß) plaques in late-stage Alzheimer disease is well defined and confirmed by in vivo PET. However, there are discrepancies between which regions contribute to the earliest topographic Aß deposition within the neocortex. Methods: This study investigated Aß 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 Aß 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 Aß deposition patterns may be of significance for diagnostics and understanding the development of Alzheimer disease phenotypes.

Assessment of Gray Matter Microstructural Alterations in Alzheimer's Disease by Free Water Imaging.

Background: Cortical neurodegenerative processes may precede the emergence of disease symptoms in patients with Alzheimer's disease (AD) by many years. No study has evaluated the free water of patients with AD using gray matter-based spatial statistics. Objective: The aim of this study was to explore cortical microstructural changes within the gray matter in AD by using free water imaging with gray matter-based spatial statistics. Methods: Seventy-one participants underwent multi-shell diffusion magnetic resonance imaging, 11C-Pittsburgh compound B positron emission tomography, and neuropsychological evaluations. The patients were divided into two groups: healthy controls (n = 40) and the AD spectrum group (n = 31). Differences between the groups were analyzed using voxel-based morphometry, diffusion tensor imaging, and free water imaging with gray matter-based spatial statistics. Results: Voxel-based morphometry analysis revealed gray matter volume loss in the hippocampus of patients with AD spectrum compared to that in controls. Furthermore, patients with AD spectrum exhibited significantly greater free water, mean diffusivity, and radial diffusivity in the limbic areas, precuneus, frontal lobe, temporal lobe, right putamen, and cerebellum than did the healthy controls. Overall, the effect sizes of free water were greater than those of mean diffusivity and radial diffusivity, and the larger effect sizes of free water were thought to be strongly correlated with AD pathology. Conclusions: This study demonstrates the utility of applying voxel-based morphometry, gray matter-based spatial statistics, free water imaging and diffusion tensor imaging to assess AD pathology and detect changes in gray matter.

Case Report: Taxifolin for neurosurgery-associated early-onset cerebral amyloid angiopathy.

Cases of iatrogenic cerebral amyloid angiopathy (CAA) have been increasingly reported recently, particularly those associated with neurosurgery. Preclinical studies have shown taxifolin to be promising for treating CAA. We describe a young 42-year-old man with a history of childhood traumatic brain injury that required a craniotomy for hematoma evacuation. He later presented with recurrent lobar intracerebral hemorrhage (ICH) decades later, which was histologically confirmed to be CAA. Serial 11C-Pittsburgh compound B positron emission tomography (11C-PiB-PET) imaging showed a 24% decrease in global standardized uptake value ratio (SUVR) at 10 months after taxifolin use. During this period, the patient experienced clinical improvement with improved consciousness and reduced recurrent ICH frequency, which may be partly attributable to the potential amyloid-ß (Aß) clearing the effect of taxifolin. However, this effect seemed to have diminished at 15 months, CAA should be considered in young patients presenting with recurrent lobar ICH with a history of childhood neurosurgery, and serial 11C-PiB-PET scans warrant further validation as a strategy for monitoring treatment response in CAA for candidate Aß-clearing therapeutic agents such as taxifolin.

Where Should I Draw the Line: PET-Driven, Data-Driven, or Manufacturer Cut-Off?

Background: The optimal cut-off for Alzheimer's disease (AD) CSF biomarkers remains controversial. Objective: To analyze the performance of cut-off points standardized by three methods: one that optimized the agreement between 11C-Pittsburgh compound B PET (a-PET) and CSF biomarkers (Aß1-42, pTau, tTau, and Aß1-42/Aß1-40 ratio) in our population, called PET-driven; an unbiased cut-off using data from a healthy research cohort, called data-driven, and that provided by the manufacturer. We also compare changes in ATN classification. Methods: CSF biomarkers measured by the LUMIPULSE G600II platform and qualitative visualization of amyloid positron emission tomography (a-PET) were performed in all the patients. We established a cut-off for each single biomarker and Aß1-42/Aß1-40 ratio that optimized their agreement with a-PET using ROC curves. Sensitivity, Specificity, and Overall Percent of Agreement are assessed using a-PET or clinical diagnosis as gold standard for every cut-off. Also, we established a data-driven cut-off from our cognitively unimpaired cohort. We then analyzed changes in ATN classification. Results: One hundred and ten patients were recruited. Sixty-six (60%) were a-PET positive. PET-driven cut-offs were: pTau > 57, tTau > 362.62, Aß1-42/Aß1-40 < 0.069. For a single biomarker, pTau showed the highest accuracy (AUC 0.926). New PET-driven cut-offs classified patients similarly to manufacturer cut-offs (only two patients changed). However, 20 patients (18%) changed when data-driven cut-offs were used. Conclusions: We established our sample's best CSF biomarkers cut-offs using a-PET as the gold standard. These cut-offs categorize better symptomatic subjects than data-driven in ATN classification, but they are very similar to the manufacturer's.

Imaging Neuroinflammation: Quantification of Astrocytosis in a Multitracer PET Approach.

The recent progress in the development of in vivo biomarkers is rapidly changing how neurodegenerative diseases are conceptualized and diagnosed and how clinical trials are designed today. Alzheimer's disease (AD) - the most common neurodegenerative disorder - is characterized by a complex neuropathology involving the deposition of extracellular amyloid-ß (Aß) plaques and intracellular neurofibrillary tangles (NFTs) of hyperphosphorylated tau proteins, accompanied by the activation of glial cells, i.e., astrocytes and microglia, and neuroinflammatory response, leading to neurodegeneration and cognitive dysfunction. An increasing diversity of positron emission tomography (PET) imaging radiotracers is available to selectively target the different pathophysiological processes of AD. Along with the success of Aß PET and the more recent tau PET imaging, there is a great interest to develop PET tracers to image glial reactivity and neuroinflammation. While most research to date has focused on imaging microgliosis, there is an upsurge of interest in imaging reactive astrocytes in the AD continuum. There is increasing evidence that reactive astrocytes are morphologically and functionally heterogeneous, with different subtypes that express different markers and display various homeostatic or detrimental roles across disease stages. Therefore, multiple biomarkers are desirable to unravel the complex phenomenon of reactive astrocytosis. In the field of in vivo PET imaging in AD, the research concerning reactive astrocytes has predominantly focused on targeting monoamine oxidase B (MAO-B), most often using either 11C-deuterium-L-deprenyl (11C-DED) or 18F-SMBT-1 PET tracers. Additionally, imidazoline2 binding (I2BS) sites have been imaged using 11C-BU99008 PET. Recent studies in our group using 11C-DED PET imaging suggest that astrocytosis may be present from the early stages of disease development in AD. This chapter provides a detailed description of the practical approach used for the analysis of 11C-DED PET imaging data in a multitracer PET paradigm including 11C-Pittsburgh compound B (11C-PiB) and 18F-fluorodeoxyglucose (18F-FDG). The multitracer PET approach allows investigating the comparative regional and temporal patterns of in vivo brain astrocytosis, fibrillar Aß deposition, glucose metabolism, and brain structural changes. It may also contribute to understanding the potential role of novel plasma biomarkers of reactive astrocytes, in particular the glial fibrillary acidic protein (GFAP), at different stages of disease progression. This chapter attempts to stimulate further research in the field, including the development of novel PET tracers that may allow visualizing different aspects of the complex astrocytic and microglial response in neurodegenerative diseases. Progress in the field will contribute to the incorporation of PET imaging of glial reactivity and neuroinflammation as biomarkers with clinical application and motivate further investigation on glial cells as therapeutic targets in AD and other neurodegenerative diseases.

Cognitive Impairment and Early-onset Cerebral Amyloid Angiopathy in a Middle-aged Man with a History of Childhood Traumatic Brain Injury.

We herein report the a 42-year-old man with early-onset cerebral amyloid angiopathy (CAA) and a history of traumatic brain injury and neurosurgery in childhood. Computed tomography revealed cognitive impairment and recurrent lobar intracerebral hemorrhaging. Magnetic resonance imaging indicated cerebral microbleeds, and Pittsburgh compound B positron emission tomography detected brain amyloid deposition, mainly in the region of trauma and occipital lobes. Interestingly, the patient had no genetic predispositions or relevant family history. This case suggests that a single traumatic brain injury or neurosurgery in childhood can cause early-onset CAA.

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.

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

AIMS: To analyze the value of 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) combined with amyloid PET in cognitive impairment diagnosis. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Cerebral amyloid deposition predicts long-term cognitive decline in hemorrhagic small vessel disease.

BACKGROUND: To investigate the association between cerebral amyloid deposition and long-term cognitive outcomes in patients with hemorrhagic small vessel disease (SVD) and survivors of intracerebral hemorrhage (ICH). METHODS: Patients experiencing an ICH without overt dementia were prospectively recruited (n = 68) for brain MRI and Pittsburgh compound B (PiB) positron emission tomography scans at baseline. Cognitive function was assessed using the mini-mental status examination (MMSE) and clinical dementia rating after an overall median follow-up of 3.8 years. A positive amyloid scan was defined as a global PiB standardized uptake value ratio >1.2. Associations between follow-up cognitive outcomes and neuroimaging markers were explored using multivariable Cox regression models. RESULTS: PiB(+) patients were older (72.1 ± 7.8 vs. 59.9 ± 11.7, p = .002) and more frequently had cerebral amyloid angiopathy (CAA) (63.6% vs. 15.8%, p = .002) than PiB(-) patients. PiB(+) was associated with a higher risk of dementia conversion (32.9 vs. 4.0 per 100-person-years, hazard ratio [HR] = 15.7 [3.0-80.7], p = .001) and MMSE score decline (58.8 vs. 9.9 per 100-person-years, HR = 6.2 [1.9-20.0], p = .002). In the non-CAA subgroup (n = 52), PiB(+) remained an independent predictor of dementia conversion, p = .04). In the Cox models, PiB(+) was an independent predictor of dementia conversion (HR = 15.8 [2.6-95.4], p = .003) and MMSE score decline (HR = 5.7 [1.6-20.3], p = .008) after adjusting for confounders. CONCLUSIONS: Cerebral amyloid deposition potentially contributes to long-term cognitive decline in SVD-related ICH.

Longitudinal changes in Alzheimer's-related plasma biomarkers and brain amyloid.

INTRODUCTION: Understanding longitudinal plasma biomarker trajectories relative to brain amyloid changes can help devise Alzheimer's progression assessment strategies. METHODS: We examined the temporal order of changes in plasma amyloid-ß ratio ( A ß 42 / A ß 40 ${{\rm A}\beta }_{42}/{{\rm A}\beta }_{40}$ ), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau ratios ( p-tau181 / A ß 42 $\text{p-tau181}/\mathrm{A}{\beta}_{42}$ , p-tau231 / A ß 42 $\text{p-tau231}/\mathrm{A}{\beta}_{42}$ ) relative to 11 C-Pittsburgh compound B (PiB) positron emission tomography (PET) cortical amyloid burden (PiB-/+). Participants (n = 199) were cognitively normal at index visit with a median 6.1-year follow-up. RESULTS: PiB groups exhibited different rates of longitudinal change in A ß 42 / A ß 40 ( ß = 5.41 × 10 - 4 , SE = 1.95 × 10 - 4 , p = 0.0073 ) ${{\rm A}\beta }_{42}/{{\rm A}\beta }_{40}\ ( {\beta \ = \ 5.41 \times {{10}}^{ - 4},{\rm{\ SE\ }} = \ 1.95 \times {{10}}^{ - 4},\ p\ = \ 0.0073} )$ . Change in brain amyloid correlated with change in GFAP (r = 0.5, 95% CI = [0.26, 0.68]). The greatest relative decline in A ß 42 / A ß 40 ${{\rm A}\beta }_{42}/{{\rm A}\beta }_{40}$ (-1%/year) preceded brain amyloid positivity by 41 years (95% CI = [32, 53]). DISCUSSION: Plasma A ß 42 / A ß 40 ${{\rm A}\beta }_{42}/{{\rm A}\beta }_{40}$ may begin declining decades prior to brain amyloid accumulation, whereas p-tau ratios, GFAP, and NfL increase closer in time. HIGHLIGHTS Plasma A ß 42 / A ß 40 ${{\rm A}\beta }_{42}/{{\rm A}\beta }_{40}$ declines over time among PiB- but does not change among PiB+. Phosphorylated-tau to Aß42 ratios increase over time among PiB+ but do not change among PiB-. Rate of change in brain amyloid is correlated with change in GFAP and neurofilament light chain. The greatest decline in A ß 42 / A ß 40 ${{\rm A}\beta }_{42}/{{\rm A}\beta }_{40}$ may precede brain amyloid positivity by decades.

Comparative examination of the pons and corpus callosum as reference regions for quantitative evaluation in positron emission tomography imaging for Alzheimer's disease using 11C-Pittsburgh Compound-B.

OBJECTIVES: Standardised uptake value ratio (SUVR) is usually obtained by dividing the SUV of the region of interest (ROI) by that of the cerebellar cortex. Cerebellar cortex is not a valid reference in cases where amyloid ß deposition or lesions are present. Only few studies have evaluated the use of other regions as references. We compared the validity of the pons and corpus callosum as reference regions for the quantitative evaluation of brain positron emission tomography (PET) using 11C-PiB compared to the cerebellar cortex. METHODS: We retrospectively evaluated data from 86 subjects with or without Alzheimer's disease (AD). All subjects underwent magnetic resonance imaging, PET imaging, and cognitive function testing. For the quantitative analysis, three-dimensional ROIs were automatically placed, and SUV and SUVR were obtained. We compared these values between AD and healthy control (HC) groups. RESULTS: SUVR data obtained using the pons and corpus callosum as reference regions strongly correlated with that using the cerebellar cortex. The sensitivity and specificity were high when either the pons or corpus callosum was used as the reference region. However, the SUV values of the corpus callosum were different between AD and HC (p < 0.01). CONCLUSIONS: Our data suggest that the pons and corpus callosum might be valid reference regions.

Longitudinal head-to-head comparison of 11C-PiB and 18F-florbetapir PET in a Phase 2/3 clinical trial of anti-amyloid-ß monoclonal antibodies in dominantly inherited Alzheimer's disease.

PURPOSE: Pittsburgh Compound-B (11C-PiB) and 18F-florbetapir are amyloid-ß (Aß) positron emission tomography (PET) radiotracers that have been used as endpoints in Alzheimer's disease (AD) clinical trials to evaluate the efficacy of anti-Aß monoclonal antibodies. However, comparing drug effects between and within trials may become complicated if different Aß radiotracers were used. To study the consequences of using different Aß radiotracers to measure Aß clearance, we performed a head-to-head comparison of 11C-PiB and 18F-florbetapir in a Phase 2/3 clinical trial of anti-Aß monoclonal antibodies. METHODS: Sixty-six mutation-positive participants enrolled in the gantenerumab and placebo arms of the first Dominantly Inherited Alzheimer Network Trials Unit clinical trial (DIAN-TU-001) underwent both 11C-PiB and 18F-florbetapir PET imaging at baseline and during at least one follow-up visit. For each PET scan, regional standardized uptake value ratios (SUVRs), regional Centiloids, a global cortical SUVR, and a global cortical Centiloid value were calculated. Longitudinal changes in SUVRs and Centiloids were estimated using linear mixed models. Differences in longitudinal change between PET radiotracers and between drug arms were estimated using paired and Welch two sample t-tests, respectively. Simulated clinical trials were conducted to evaluate the consequences of some research sites using 11C-PiB while other sites use 18F-florbetapir for Aß PET imaging. RESULTS: In the placebo arm, the absolute rate of longitudinal change measured by global cortical 11C-PiB SUVRs did not differ from that of global cortical 18F-florbetapir SUVRs. In the gantenerumab arm, global cortical 11C-PiB SUVRs decreased more rapidly than global cortical 18F-florbetapir SUVRs. Drug effects were statistically significant across both Aß radiotracers. In contrast, the rates of longitudinal change measured in global cortical Centiloids did not differ between Aß radiotracers in either the placebo or gantenerumab arms, and drug effects remained statistically significant. Regional analyses largely recapitulated these global cortical analyses. Across simulated clinical trials, type I error was higher in trials where both Aß radiotracers were used versus trials where only one Aß radiotracer was used. Power was lower in trials where 18F-florbetapir was primarily used versus trials where 11C-PiB was primarily used. CONCLUSION: Gantenerumab treatment induces longitudinal changes in Aß PET, and the absolute rates of these longitudinal changes differ significantly between Aß radiotracers. These differences were not seen in the placebo arm, suggesting that Aß-clearing treatments may pose unique challenges when attempting to compare longitudinal results across different Aß radiotracers. Our results suggest converting Aß PET SUVR measurements to Centiloids (both globally and regionally) can harmonize these differences without losing sensitivity to drug effects. Nonetheless, until consensus is achieved on how to harmonize drug effects across radiotracers, and since using multiple radiotracers in the same trial may increase type I error, multisite studies should consider potential variability due to different radiotracers when interpreting Aß PET biomarker data and, if feasible, use a single radiotracer for the best results. TRIAL REGISTRATION: ClinicalTrials.gov NCT01760005. Registered 31 December 2012. Retrospectively registered.

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.

BACKGROUND: Comparisons of late-onset Alzheimer's disease (LOAD) and autosomal dominant AD (ADAD) are confounded by age. METHODS: 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. RESULTS: At baseline, MCs had the lowest age-adjusted level of CSF Aß42 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. DISCUSSION: Preclinical ADAD and LOAD share many biomarker signatures, but cross-sectional and longitudinal differences may exist.

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

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

In Vivo Preclinical Assessment of ß-Amyloid-Affine [11C]C-PIB Accumulation in Aluminium-Induced Alzheimer's Disease-Resembling Hypercholesterinaemic Rat Model.

Aluminum (Al) excess and hypercholesterinaemia are established risks of Alzheimer's disease (AD). The aim of this study was to establish an AD-resembling hypercholesterinaemic animal model-with the involvement of 8 week and 48 week-old Fischer-344 rats-by Al administration for the safe and rapid verification of ß-amyloid-targeted positron emission tomography (PET) radiopharmaceuticals. Measurement of lipid parameters and ß-amyloid-affine [11C]C-Pittsburgh Compound B ([11C]C-PIB) PET examinations were performed. Compared with the control, the significantly elevated cholesterol and LDL levels of the rats receiving the cholesterol-rich diet support the development of hypercholesterinaemia (p ≤ 0.01). In the older cohort, a notably increased age-related radiopharmaceutical accumulation was registered compared to in the young (p ≤ 0.05; p ≤ 0.01). A monotherapy-induced slight elevation of mean standardised uptake values (SUVmean) was statistically not significant; however, adult rats administered a combined diet expressed remarkable SUVmean increment compared to the adult control (SUVmean: from 0.78 ± 0.16 to 1.99 ± 0.28). One and two months after restoration to normal diet, the cerebral [11C]C-PIB accumulation of AD-mimicking animals decreased by half and a third, respectively, to the baseline value. The proposed in vivo Al-induced AD-resembling animal system seems to be adequate for the understanding of AD neuropathology and future drug testing and radiopharmaceutical development.

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.

A pilot study comparing myelin measurements from myelin water imaging and 11C-PIB PET in multiple sclerosis.

MRI-based myelin water fraction (MWF) and PET-based Pittsburgh compound B (PiB) imaging both have potential to measure myelin in multiple sclerosis (MS). We characterised the differences in MWF and PiB binding in MS lesions relative to normal-appearing white matter and assessed the correlation between MWF and PiB binding in 11 MS participants and 3 healthy controls within 14 white matter regions of interest. Both PiB binding and MWF were reduced in MS lesions relative to NAWM, and a modest within subject correlation between MWF and PiB binding was found. This pilot study shows that MWF and PET-PiB provide different information about myelin loss in MS.

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.

Association of B cell profile and receptor repertoire with the progression of Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent type of dementia. Reports have revealed that the peripheral immune system is linked to neuropathology; however, little is known about the contribution of B lymphocytes in AD. For this longitudinal study, 133 participants are included at baseline and second-year follow-up. Also, we analyze B cell receptor (BCR) repertoire data generated from a public dataset of three normal and 10 AD samples and perform BCR repertoire profiling and pairwise sharing analysis. As a result, longitudinal increase in B lymphocytes is associated with increased cerebral amyloid deposition and hyperactivates induced pluripotent stem cell-derived microglia with loss-of-function for beta-amyloid clearance. Patients with AD share similar class-switched BCR sequences with identical isotypes, despite the high somatic hypermutation rate. Thus, BCR repertoire profiling can lead to the development of individualized immune-based therapeutics and treatment. We provide evidence of both quantitative and qualitative changes in B lymphocytes during AD pathogenesis.

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

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