Pittsburgh Compound B Binding Research Articles

Amyloid imaging of Lewy body‐associated disorders

Clinicopathologic studies of Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB) commonly reveal abnormal β-amyloid deposition in addition to diffuse Lewy bodies (α-synuclein aggregates), but the relationship among these neuropathologic features and the development of dementia in these disorders remains uncertain. The purpose of this study was to determine whether amyloid-β deposition detected by PET imaging with Pittsburgh Compound B (PIB) distinguishes clinical subtypes of Lewy body-associated disorders. Nine healthy controls, 8 PD with no cognitive impairment, 9 PD with mild cognitive impairment, 6 DLB, and 15 PDD patients underwent [(11)C]-PIB positron emission tomography imaging, clinical examination, and cognitive testing. The binding potential (BP) of PIB for predefined regions and the mean cortical BP (MCBP) were calculated for each participant. Annual longitudinal follow-up and postmortem examinations were performed on a subset of participants. Regional PIB BPs and the proportion of individuals with abnormally elevated MCBP were not significantly different across participant groups. Elevated PIB binding was associated with worse global cognitive impairment in participants with Lewy body disorders but was not associated with any other clinical or neuropsychological features, including earlier onset or faster rate of progression of cognitive impairment. These results suggest that the presence of fibrillar amyloid-β does not distinguish between clinical subtypes of Lewy body-associated disorders, although larger numbers are needed to more definitively rule out this association. Amyloid-β may modify the severity of global cognitive impairment in individuals with Lewy body-associated dementia.

Exercise and Alzheimer's disease biomarkers in cognitively normal older adults

In addition to the increasingly recognized role of physical exercise in maintaining cognition, exercise may influence Alzheimer's disease (AD) pathology, as transgenic mouse studies show lowered levels of AD pathology in exercise groups. The objective of this study was to elucidate the association between exercise and AD pathology in humans using Pittsburgh compound-B (PIB), amyloid-beta (Abeta)(42), tau, and phosphorylated tau (ptau)(181) biomarkers. Sixty-nine older adults (17 males, 52 females) aged 55 to 88 years, were recruited and confirmed to be cognitively normal. A questionnaire on physical exercise levels over the past decade was administered to all. Cerebrospinal fluid samples were collected from 56 participants, and amyloid imaging with PIB was performed on 54 participants. Participants were classified based on biomarker levels. Those with elevated PIB (p = 0.030), tau (p = 0.040), and ptau(181) (p = 0.044) had significantly lower exercise, with a nonsignificant trend for lower Abeta(42) (p = 0.135) to be associated with less exercise. Results were similar for PIB after controlling for covariates; tau (p = 0.115) and ptau(181) (p = 0.123) differences were reduced to nonsignificant trends. Additional analyses also demonstrated that active individuals who met the exercise guidelines set by the American Heart Association had significantly lower PIB binding and higher Abeta(42) levels with and without controlling for covariates (PIB: p = 0.006 and p = 0.001; Abeta(42): p = 0.042 and p = 0.046). Last, the associations between exercise engagement and PIB levels were more prominent in APOE epsilon 4 noncarriers. Collectively, these results are supportive of an association between exercise engagement and AD biomarkers in cognitively normal older adults.

Increased metabolic vulnerability in early-onset Alzheimer’s disease is not related to amyloid burden

Patients with early age-of-onset Alzheimer's disease show more rapid progression, more generalized cognitive deficits and greater cortical atrophy and hypometabolism compared to late-onset patients at a similar disease stage. The biological mechanisms that underlie these differences are not well understood. The purpose of this study was to examine in vivo whether metabolic differences between early-onset and late-onset Alzheimer's disease are associated with differences in the distribution and burden of fibrillar amyloid-beta. Patients meeting criteria for probable Alzheimer's disease (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's; Disease and Related Disorders Association criteria) were divided based on estimated age at first symptom (less than or greater than 65 years) into early-onset (n = 21, mean age-at-onset 55.2 +/- 5.9 years) and late-onset (n = 18, 72.0 +/- 4.7 years) groups matched for disease duration and severity. Patients underwent positron emission tomography with the amyloid-beta-ligand [(11)C]-labelled Pittsburgh compound-B and the glucose analogue [(18)F]-labelled fluorodeoxyglucose. A group of cognitively normal controls (n = 30, mean age 73.7 +/- 6.4) was studied for comparison. [(11)C]-labelled Pittsburgh compound-B images were analysed using Logan graphical analysis (cerebellar reference) and [(18)F]-labelled fluorodeoxyglucose images were normalized to mean activity in the pons. Group differences in tracer uptake were assessed on a voxel-wise basis using statistical parametric mapping, and by comparing mean values in regions of interest. To account for brain atrophy, analyses were repeated after applying partial volume correction to positron emission tomography data. Compared to normal controls, both early-onset and late-onset Alzheimer's disease patient groups showed increased [(11)C]-labelled Pittsburgh compound-B uptake throughout frontal, parietal and lateral temporal cortices and striatum on voxel-wise and region of interest comparisons (P < 0.05). However, there were no significant differences in regional or global [(11)C]-labelled Pittsburgh compound-B binding between early-onset and late-onset patients. In contrast, early-onset patients showed significantly lower glucose metabolism than late-onset patients in precuneus/posterior cingulate, lateral temporo-parietal and occipital corticies (voxel-wise and region of interest comparisons, P < 0.05). Similar results were found for [(11)C]-labelled Pittsburgh compound-B and [(18)F]-labelled fluorodeoxyglucose using atrophy-corrected data. Age-at-onset correlated positively with glucose metabolism in precuneus, lateral parietal and occipital regions of interest (controlling for age, education and Mini Mental State Exam, P < 0.05), while no correlations were found between age-at-onset and [(11)C]-labelled Pittsburgh compound-B binding. In summary, a comparable burden of fibrillar amyloid-beta was associated with greater posterior cortical hypometabolism in early-onset Alzheimer's disease. Our data are consistent with a model in which both early amyloid-beta accumulation and increased vulnerability to amyloid-beta pathology play critical roles in the pathogenesis of Alzheimer's disease in young patients.

Pittsburgh compound B binding in poststroke dementia

We hypothesize that Pittsburgh compound B (PIB) binding is common in poststroke dementia (PSD) and that cognitive decline may be faster in PIB positive patients. We performed PIB positron emission tomography (PET) among 17 subjects: 10 PSD patients, 4 Alzheimer's disease (AD) patients, and 3 healthy controls. We also compared the rate of change in mini-mental state examination (MMSE) between PIB positive and negative patients. We detected AD-like PIB binding in 4 PSD patients (40%), all the AD patients, and 1 healthy control. The global PIB retention standardized uptake value (SUV) at 35–45 min for PIB positive stroke patients was 1.67 (range 1.56–1.82), which was similar to the AD patients (1.65; range 1.46–1.88) and was lower than PIB negative patients (1.29, range 1.24–1.34). Mean annual MMSE decline for the 4 PIB positive patients was 2.9 and that for the 6 PIB negative patients was 1. This pilot study suggests that PIB PET is feasible for the evaluation of PSD and PIB binding may be common in PSD. Whether presence of PIB binding is associated with a more rapid cognitive decline in PSD requires further study to confirm.

Differential association of [ 11 C]PIB and [ 18 F]FDDNP binding with cognitive impairment

To evaluate associations of [(11)C]Pittsburgh compound B (PIB) and [(18)F]FDDNP with impairment in specific cognitive domains over the broader spectrum comprising cognitively normal elderly subjects, patients with mild cognitive impairment (MCI), and patients with Alzheimer disease (AD). Twelve patients with AD, 13 patients with MCI, and 15 cognitively normal elderly subjects were included. Paired [(11)C]PIB and [(18)F]FDDNP PET scans were performed in all subjects. Binding potential (BP(ND)) was calculated using parametric images of BP(ND) for global, frontal, parietal, and temporal cortex; medial temporal lobe; and posterior cingulate. Cognitive functions were assessed using a battery of neuropsychological tests. Linear regression analyses were used to assess associations of [(11)C]PIB and [(18)F]FDDNP binding with cognitive measures. Adjusted for age, sex, and [(18)F]FDDNP binding, higher global [(11)C]PIB binding was associated with lower scores on the Mini-Mental State Examination, immediate and delayed recall of the Rey Auditory Verbal Learning Task (RAVLT), Visual Association Task, and Trail Making Test part B. Conversely, higher [(18)F]FDDNP binding was independently associated with lower scores on immediate recall of the RAVLT. After additional adjustment for diagnosis, higher [(11)C]PIB binding remained independently associated with delayed recall (standardized beta = -0.39, p = 0.01), whereas higher [(18)F]FDDNP binding remained independently associated with immediate recall (standardized beta = -0.32, p = 0.03). When regional binding was assessed using stepwise models, both increased frontal [(11)C]PIB and temporal [(18)F]FDDNP binding were associated with memory, whereas increased parietal [(11)C]PIB binding was associated with nonmemory functions. Increased [(18)F]FDDNP binding is specifically associated with impairment of episodic memory, whereas increased [(11)C]Pittsburgh compound B binding is associated with impairment in a broader range of cognitive functions.

Cortical Binding of Pittsburgh Compound B, an Endophenotype for Genetic Studies of Alzheimer's Disease

To date, all known Alzheimer's disease genes influence amyloid beta (Abeta). Imaging of Abeta deposition in the human brain using Pittsburgh Compound B (PIB) offers the possibility of using cortical PIB binding as a quantitative endophenotype for genetic studies of late-onset Alzheimer's disease (LOAD). Heritability of Abeta deposition was determined using 82 elderly siblings from 35 families. Correlation with other Abeta related traits was determined using an unrelated sample of 112 individuals. For both samples, apolipoprotein E (APOE) epsilon4 was genotyped and positron emission tomography imaging was performed using the PIB ligand. Mean cortical binding potential (MCBP) was computed from several regions of interest. MCBP has a high heritability (.61, p = .043). Furthermore, 74% of the heritable component cannot be explained by APOE epsilon4 genotype. The unrelated sample reveals that a third of the variance of MCBP cannot be predicted by other biological traits, including cerebrospinal fluid (CSF) amyloid beta 42 (Abeta42) levels. These findings demonstrate that MCBP is a genetic trait and that other more easily measured Abeta related traits such as CSF Abeta42 do not fully explain the variance in MCBP. Thus, MCBP is a useful trait for large-scale genetic studies of LOAD.

Cerebrospinal fluid tau and ptau 181 increase with cortical amyloid deposition in cognitively normal individuals: Implications for future clinical trials of Alzheimer's disease

Alzheimer's disease (AD) pathology is estimated to develop many years before detectable cognitive decline. Fluid and imaging biomarkers may identify people in early symptomatic and even preclinical stages, possibly when potential treatments can best preserve cognitive function. We previously reported that cerebrospinal fluid (CSF) levels of amyloid-β42 (Aβ42) serve as an excellent marker for brain amyloid as detected by the amyloid tracer, Pittsburgh compound B (PIB). Using data from 189 cognitively normal participants, we now report a positive linear relationship between CSF tau/ptau181 (primary constituents of neurofibrillary tangles) with the amount of cortical amyloid. We observe a strong inverse relationship of cortical PIB binding with CSF Aβ42 but not for plasma Aβ species. Some individuals have low CSF Aβ42 but no cortical PIB binding. Together, these data suggest that changes in brain Aβ42 metabolism and amyloid formation are early pathogenic events in AD, and that significant disruptions in CSF tau metabolism likely occur after Aβ42 initially aggregates and increases as amyloid accumulates. These findings have important implications for preclinical AD diagnosis and treatment.

Amyloid imaging in mild cognitive impairment subtypes.

We utilized the amyloid imaging ligand Pittsburgh Compound B (PiB) to determine the presence of Alzheimer's disease (AD) pathology in different mild cognitive impairment (MCI) subtypes and to relate increased PiB binding to other markers of early AD and longitudinal outcome. Twenty-six patients with MCI (13 single-domain amnestic-MCI [a-MCI], 6 multidomain a-MCI, and 7 nonamnestic MCI) underwent PiB imaging. Twenty-three had clinical follow-up (21.2 +/- 16.0 [standard deviation] months) subsequent to their PiB scan. Using cutoffs established from a control cohort, we found that 14 (54%) patients had increased levels of PiB retention and were considered "amyloid-positive." All subtypes were associated with a significant proportion of amyloid-positive patients (6/13 single-domain a-MCI, 5/6 multidomain a-MCI, 3/7 nonamnestic MCI). There were no obvious differences in the distribution of PiB retention in the nonamnestic MCI group. Predictors of conversion to clinical AD in a-MCI, including poorer episodic memory, and medial temporal atrophy, were found in the amyloid-positive relative to amyloid-negative a-MCI patients. Longitudinal follow-up demonstrated 5 of 13 amyloid-positive patients, but 0 of 10 amyloid-negative patients, converted to clinical AD. Further, 3 of 10 amyloid-negative patients "reverted to normal." These data support the notion that amyloid-positive patients are likely to have early AD, and that the use of amyloid imaging may have an important role in determining which patients are likely to benefit from disease-specific therapies. In addition, our data are consistent with longitudinal studies that suggest a significant percentage of all MCI subtypes will develop AD.

PIB binding in aged primate brain: Enrichment of high-affinity sites in humans with Alzheimer's disease

Aged nonhuman primates accumulate large amounts of human-sequence amyloid β (Aβ) in the brain, yet they do not manifest the full phenotype of Alzheimer's disease (AD). To assess the biophysical properties of Aβ that might govern its pathogenic potential in humans and nonhuman primates, we incubated the benzothiazole imaging agent Pittsburgh Compound B (PIB) with cortical tissue homogenates from normal aged humans, humans with AD, and from aged squirrel monkeys, rhesus monkeys, and chimpanzees with cerebral Aβ-amyloidosis. Relative to humans with AD, high-affinity PIB binding is markedly reduced in cortical extracts from aged nonhuman primates containing levels of insoluble Aβ similar to those in AD. The high-affinity binding of PIB may be selective for a pathologic, human-specific conformation of multimeric Aβ, and thus could be a useful experimental tool for clarifying the unique predisposition of humans to Alzheimer's disease.

P2-067: PIB binding in Alzheimer's disease and nonhuman primate brain

Background: The amyloid cascade hypothesis implicates the Abeta peptide as an upstream effector in Alzheimer’s disease (AD) neurodegeneration. However, the deposition of Abeta in the human brain is not always associated with frank dementia, inasmuch as abundant Abeta lesions are sometimes found in the brains of aged humans without overt cognitive impairment. Furthermore, age-related accumulation of cerebral Abeta is commonly observed in nonhuman primates, yet no nonhuman species has been shown to exhibit the full behavioral or pathological characteristics of AD. Because of their close biological relationship to humans, nonhuman primates are a unique model of nonpathologic Abeta accumulation. We have extensively characterized cerebral Abeta populations in AD, aged chimpanzees, rhesus macaques, and squirrel monkeys. Methods: Using immunohistochemistry, ELISA, immunoprecipitation/ MALDI-TOF MS and in vivo Abeta-seeding assays, we found that Abeta populations are quantitatively and qualitatively similar in AD and nonhuman primate brain. To explain the pathological differences between humans and other primates, we hypothesized that higher-order structural features distinguish toxic Abeta in AD brain from the relatively benign Abeta in nonhuman primates. Recent reports show that Pittsburgh Compound B (PIB), a radioligand used for in vivo PET imaging of amyloid, binds with high affinity and stoichiometry to AD brain but with low stoichiometry to synthetic Abeta and to the Abeta deposits in transgenic mouse brain. We measured the binding of 3H-PIB to cortical homogenates from AD and nonhuman primate cases, all of which had been characterized for total soluble and insoluble Abeta levels. Results: We found that 3H-PIB binds with low stoichiometry to Abeta in nonhuman primate cortical homogenates, even in cases with levels of Abeta equal to those in AD. Conclusions: These data suggest that cerebral beta-amyloid deposits in aged nonhuman primates, which naturally develop cerebral beta-amyloidosis over the course of many years, are structurally distinct from those in humans with AD, and that high-affinity PIB binding may be relatively selective for pathogenic Abeta in the AD brain.

Brain Volume Decline in Aging

To assess the relation between socioeconomic status (SES) and structural brain change in nondemented older adults and to ascertain the potential role of preclinical Alzheimer disease (AD). Cross-sectional and longitudinal observation. Alzheimer's Disease Research Center, St Louis, Missouri. Volunteer sample of 362 nondemented adults aged 18 to 93 years. The main cohort of 100 was evaluated for dementia and SES; a Clinical Dementia Rating (CDR) of 0 (no dementia) and middle, high-middle, or high SES was required for eligibility. All 362 received magnetic resonance imaging; of the main 100, 91 received follow-up clinical assessment, and 33 received follow-up magnetic resonance imaging over at least a 3-year interval. A separate sample of 58 CDR 0 participants (aged 47 to 86 years) took part in amyloid imaging with Pittsburgh Compound B (PiB) labeled with radioactive carbon ((11)C). Whole-brain volume adjusted for head size (aWBV) and change per year. aWBV declined by 0.22% per year between the ages of 20 and 80 years with accelerated decline in advanced aging. Controlling for effects of age and sex in older adults (>65 years) with CDR 0, higher SES was associated with smaller aWBV (3.8% difference spanning the sample range from middle to high privilege, P< .01) and more rapid volume loss (0.39% per year to 0.68% per year from middle to high privilege, P< .05). aWBV was reduced by 2.5% in individuals positive for PiB binding (n=9) as compared with individuals negative for PiB binding (n=49, P< .05), supporting an influence of undetected preclinical AD. Follow-up clinical data revealed that brain volume reduction associated with SES was greater in those who later developed very mild dementia (preclinical CDR 0 group, n=19) compared with those who remained nondemented (stable CDR 0 group, n=64; group x SES interaction, P< .05). Privileged nondemented older adults harbor more preclinical brain atrophy, consistent with their having greater reserve against the expression of AD.

In VitroCharacterization of Pittsburgh Compound-B Binding to Lewy Bodies

Dementia with Lewy bodies (DLB) is pathologically characterized by the presence of alpha-synuclein-containing Lewy bodies within the neocortical, limbic, and paralimbic regions. Like Alzheimer's disease (AD), Abeta plaques are also present in most DLB cases. The contribution of Abeta to the development of DLB is unclear. [11C]-Pittsburgh compound B ([11C]-PIB) is a thioflavin-T derivative that has allowed in vivo Abeta burden to be quantified using positron emission tomography (PET). [11C]-PIB PET studies have shown similar high cortical [11C]-PIB binding in AD and DLB subjects. To establish the potential binding of PIB to alpha-synuclein in DLB patients, we characterized the in vitro binding of PIB to recombinant human alpha-synuclein and DLB brain homogenates. Analysis of the in vitro binding studies indicated that [3H]-PIB binds to alpha-synuclein fibrils but with lower affinity than that demonstrated/reported for Abeta(1-42) fibrils. Furthermore, [3H]-PIB was observed to bind to Abeta plaque-containing DLB brain homogenates but failed to bind to DLB homogenates that were Abeta plaque-free ("pure DLB"). Positive PIB fluorescence staining of DLB brain sections colocalized with immunoreactive Abeta plaques but failed to stain Lewy bodies. Moreover, image quantification analysis suggested that given the small size and low density of Lewy bodies within the brains of DLB subjects, any contribution of Lewy bodies to the [11C]-PIB PET signal would be negligible. These studies indicate that PIB retention observed within the cortical gray matter regions of DLB subjects in [11C]-PIB PET studies is largely attributable to PIB binding to Abeta plaques and not Lewy bodies.

Imaging β-amyloid burden in aging and dementia

To compare brain beta-amyloid (Abeta) burden measured with [(11)C]Pittsburgh Compound B (PIB) PET in normal aging, Alzheimer disease (AD), and other dementias. Thirty-three subjects with dementia (17 AD, 10 dementia with Lewy bodies [DLB], 6 frontotemporal dementia [FTD]), 9 subjects with mild cognitive impairment (MCI), and 27 age-matched healthy control subjects (HCs) were studied. Abeta burden was quantified using PIB distribution volume ratio. Cortical PIB binding was markedly elevated in every AD subject regardless of disease severity, generally lower and more variable in DLB, and absent in FTD, whereas subjects with MCI presented either an "AD-like" (60%) or normal pattern. Binding was greatest in the precuneus/posterior cingulate, frontal cortex, and caudate nuclei, followed by lateral temporal and parietal cortex. Six HCs (22%) showed cortical uptake despite normal neuropsychological scores. PIB binding did not correlate with dementia severity in AD or DLB but was higher in subjects with an APOE-epsilon4 allele. In DLB, binding correlated inversely with the interval from onset of cognitive impairment to diagnosis. Pittsburgh Compound B PET findings match histopathologic reports of beta-amyloid (Abeta) distribution in aging and dementia. Noninvasive longitudinal studies to better understand the role of amyloid deposition in the course of neurodegeneration and to determine if Abeta deposition in nondemented subjects is preclinical AD are now feasible. Our findings also suggest that Abeta may influence the development of dementia with Lewy bodies, and therefore strategies to reduce Abeta may benefit this condition.

O3-06-08: Pattern of amyloid plaque deposition with Pittsburgh compound-B (PIB) in mild cognitive impairment

quantified by distribution volume ratio (DVR). Results: Neocortical A deposition was present in 100% of AD subjects, 89% of DLB subjects, 43% of MCI subjects, 18% of elderly controls and no FTD subjects. PIB distribution was similar in AD and DLB, being greatest in medial frontal, precuneus, parietal and lateral temporal cortex, and caudate nuclei. Occipital, sensori-motor and mesial temporal cortex were less affected. Neocortical DVR measured 2.0 0.3 in AD, 1.6 0.3 in DLB, 1.5 0.4 in MCI, 1.2 0.2 in control and 1.1 0.1 in FTD subjects (p 0.01 for all differences). Five of the NC had cortical binding predominantly in frontal cortex with one progressing to MCI at 12-month follow-up. DVR correlated with MMSE and memory impairment across all subjects (r 0.7, p 0.0001) but not within groups (in AD group p 0.16), and with a shorter interval from onset of cognitive impairment to diagnosis in DLB (r 0.9, p 0.002). Conclusions: PIB PET will permit earlier diagnosis of AD and improve differential diagnosis of dementia. Longitudinal follow-up is required to determine the significance of the PIB binding in the normal elderly controls and MCI subjects. Our findings suggest that PIB PET will detect AD before demonstrable cognitive decline and therefore be a useful tool for early intervention trials.

Aging Is Not Synonymous With Alzheimer's Disease

ANAHEIM, CALIF. — “Aging and Alzheimer's disease are not synonymous,” Dr. John C. Morris told attendees at the Advances in Alzheimer's session at the 2006 joint conference of the American Society on Aging and the National Council on Aging. Dr. Morris, the Friedman Distinguished Professor of Neurology at Washington University, St. Louis, contends that Alzheimer's disease (AD) is not an inevitable consequence of aging. “Truly, healthy patients have cognitive mental abilities that remain surprisingly intact,” he said. During healthy aging, an individual gets more easily distracted, cannot multitask as well, and takes longer to perform a given task, but the task is still done accurately. The prevalence of AD among Americans is 5% at age 65, and doubles for every 5 years of age over 65, according to Dr. Morris. Even so, by age 85, only 50% of the population has AD, leaving many a healthy senior. “In truly healthy aging, an individual can be quite vibrant, even to age 100,” Dr. Morris said. Dr. Morris also contends that AD is not only treatable but also preventable. Drugs that are being tested in clinical trials inhibit production or promote degradation and clearance of amyloid-β, the protein that forms plaques in AD patients' brains. “If we wanted to stop AD, we have the potential candidates. All we need to do is evaluate them to find out which are safe and effective,” Dr. Morris stated. AD is both underdiagnosed and undertreated. Of approximately 4.5 million Americans diagnosed with AD, only 2.8 million (62%) have received a definite diagnosis. Of those, only half are being treated with cholinesterase inhibitors (ChEIs). By the time AD patients are diagnosed, on average, 60% of their brain cells already are damaged, Dr. Morris said. He added that that justifies use of prophylactic treatment in individuals with mild cognitive impairment (MCI), who are at high risk of Alzheimer's. According to the guidelines of the American Academy of Neurology (Neurology 2001;56:1154–66), ChEIs such as donepezil (Aricept) are the standard treatment for dementia, and high-dose vitamin E is recommended. Newer drugs, such as memantine (Namenda), also are useful. Dr. Morris said ChEIs are cost effective for patients with MCI; although the drugs are not a cure, they can slow dementia or help patients maintain their mental functioning. Another preventive approach would be to develop an AD vaccine. Dr. James A.R. Nicoll and colleagues tested an AD vaccine in a single patient and compared the response to seven control subjects (Nat. Med. 2003;9:448–52). Based on in vivo imaging, the vaccine apparently cleared amyloid-β from the brain of the immunized participant, but Dr. Morris said there was no evidence that the vaccine benefited the patient clinically. He described one cutting-edge diagnostic technique using Pittsburgh compound B (PIB), a PET tracer used for in vivo imaging of amyloid-β plaques (Ann. Neurol. 2004;55:306–19). In 9 of 10 individuals with AD, the PIB binding potential was consistently higher than in healthy controls. PIB binding and CSF amyloid-β concentrations corresponded to clinical diagnosis of Alzheimer's (Ann. Neurol. 2006;59:512–9). Investigators have identified certain biomarkers in patients with MCI that may predict AD development using a variety of techniques (amyloid-βconcentrations in blood plasma, neuroimaging, functional imaging with functional MRI, PET, or single-photon emission computed tomography). “Increasingly, we are able to detect the subset of patients with mild cognitive impairment who will progress to AD,” Dr. Morris said.

Beta-Amyloid Findings Could Be Alzheimer's Marker

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessBeta-Amyloid Findings Could Be Alzheimer's MarkerAaron LevinAaron LevinSearch for more papers by this authorPublished Online:3 Feb 2006https://doi.org/10.1176/pn.41.3.0020The Holy Grail for researchers studying Alzheimer's disease is an imaging system or biomarker to help diagnose the illness or at least document its progress.A new study from researchers at Washington University in St. Louis takes a step in that direction by combining PET scan imaging and cerebrospinal fluid (CSF) analysis. The process compared the extent of beta-amyloid plaques in the brain with levels of related protein fragments in CSF or blood plasma.Using PET technology, researchers led by Anne Fagan, Ph.D., a research associate professor of neurology at the Washington University School of Medicine, scanned the brains of 24 people aged 48 to 83 to find concentrations of plaques containing beta-amyloid. They used an amyloid-binding agent, Pittsburgh Compound B (PIB), provided by investigators at the University of Pittsburgh. Some participants were cognitively normal while others had very mild, mild, or moderate dementia.Fagan and her colleagues from the Washington University Alzheimer's Disease Research Center also tested CSF and blood plasma for several proteins using enzyme-linked immunosorbent assays.They found no relation between PIB binding and the proteins amyloid-40, tau, phosphor-tau181 in CSF, and amyloid-40 and amyloid-42 in plasma. However, they did observe an inverse relationship between amyloid-42 in CSF and PIB binding at beta-amyloid plaques in the brain.“Subjects fell into two nonoverlapping groups: those with positive PIB binding had the lowest CSF amyloid-42 level, and those with negative PIB binding had the highest level,” wrote the researchers in an online publication of their paper in the Annals of Neurology.Seven subjects showed positive PIB binding and low CSF amyloid-42 levels. Three of those subjects were diagnosed with mild or moderate Alzheimer's-type dementia, and another with very mild symptoms.However, three participants were cognitively normal but had high PIB binding and low CSF levels of amyloid-42, hinting that they were in such a preclinical state. If these subjects eventually develop dementia, this combined technique may indeed prove useful for identifying cases before they reach clinical status. However, if patients such as these never decline cognitively, it may show that plaque number does not always predict the disease.Prior animal studies have suggested that amyloid plaques in the brain may bind beta-amyloid, reducing the movement of soluble beta-amyloid between the brain and the CSF, possibly accounting for the inverse relationship, said the authors. Heavy deposits of beta-amyloid plaques at autopsy are diagnostic for Alzheimer's disease.“These observations suggest that brain amyloid deposition results in low CSF amyloid-42 and that amyloid imaging and CSF amyloid-42 levels may potentially serve as antecedent biomarkers of preclinical Alzheimer's disease,” Fagan said. “[They] support the hypothesis that amyloid deposition in the brain acts as a `sink,' resulting in a new equilibrium between soluble and deposited amyloid-42 in the central nervous system.”“These measures hold potential for identifying individuals with Alzheimer's disease pathology before cognitive symptoms [appear], improving the accuracy of clinical diagnosis, and facilitating the testing of future therapies,” said Fagan in a prepared statement. “But it is important to recognize that this is still a research study, and the findings must be carefully validated before this approach can be considered for clinical use.”“We presently don't have fully validated imaging or biomarker measures that can help us monitor the development or progression of Alzheimer's in living people,” commented Neil Buckholtz, Ph.D., chief of the Dementias of Aging Branch at the National Institute on Aging. “This study represents one step in the progress being made toward identifying clinically useful biological measures for AD.”The study was supported by the National Institute on Aging and the Washington University General Clinical Research Center, which is funded by the National Institutes of Health.An abstract of “Inverse Relation Between in Vivo Amyloid Imaging Load and Cerebrospinal Fluid A42 in Humans” is posted at<www3.interscience.wiley.com/cgi-bin/abstract/112219062/ABSTRACT>.▪ ISSUES NewArchived

Binding of the Positron Emission Tomography Tracer Pittsburgh Compound-B Reflects the Amount of Amyloid-β in Alzheimer's Disease Brain But Not in Transgenic Mouse Brain

During the development of in vivo amyloid imaging agents, an effort was made to use micro-positron emission tomography (PET) imaging in the presenilin-1 (PS1)/amyloid precursor protein (APP) transgenic mouse model of CNS amyloid deposition to screen new compounds and further study Pittsburgh Compound-B (PIB), a PET tracer that has been shown to be retained well in amyloid-containing areas of Alzheimer's disease (AD) brain. Unexpectedly, we saw no significant retention of PIB in this model even at 12 months of age when amyloid deposition in the PS1/APP mouse typically exceeds that seen in AD. This study describes a series of ex vivo and postmortem in vitro studies designed to explain this low retention. Ex vivo brain pharmacokinetic studies confirmed the low in vivo PIB retention observed in micro-PET experiments. In vitro binding studies showed that PS1/APP brain tissue contained less than one high-affinity (K(d) = 1-2 nm) PIB binding site per 1000 molecules of amyloid-beta (Abeta), whereas AD brain contained >500 PIB binding sites per 1000 molecules of Abeta. Synthetic Abeta closely resembled PS1/APP brain in having less than one high-affinity PIB binding site per 1000 molecules of Abeta, although the characteristics of the few high-affinity PIB binding sites found on synthetic Abeta were very similar to those found in AD brain. We hypothesize that differences in the time course of deposition or tissue factors present during deposition lead to differences in secondary structure between Abeta deposited in AD brain and either synthetic Abeta or Abeta deposited in PS1/APP brain.