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1.  Correlation of amyloid PET ligand florbetapir F 18 (18F-AV-45) binding with β-amyloid aggregation and neuritic plaque deposition in postmortem brain tissue 
Florbetapir F 18 (18F-AV-45) is a positron emission tomography (PET) imaging ligand for the detection of amyloid aggregation associated with Alzheimer’s disease. Earlier data showed that florbetapir F 18 binds with high affinity to β-amyloid plaques in human brain homogenates (Kd = 3.7 nM) and has favorable imaging pharmacokinetic properties, including rapid brain penetration and washout. The present study used human autopsy brain tissue to evaluate the correlation between in vitro florbetapir F 18 binding and β-amyloid density measured by established neuropathological methods.
The localization and density of florbetapir F 18 binding in frozen and formalin-fixed paraffin-embedded sections of postmortem brain tissue from 40 subjects with a varying degree of neurodegenerative pathology was assessed by standard florbetapir F 18 autoradiography and correlated with the localization and density of β-amyloid identified by silver staining, thioflavin S staining, and immunohistochemistry.
There were strong quantitative correlations between florbetapir F 18 tissue binding and both β-amyloid plaques identified by light microscopy (sliver staining and thioflavin S fluorescence) and by immunohistochemical measurements of β-amyloid using three antibodies recognizing different epitopes of the β-amyloid peptide (Aβ). Florbetapir F 18 did not bind to neurofibrillary tangles.
Florbetapir F 18 selectively binds β-amyloid in human brain tissue. The binding intensity was quantitatively correlated with the density of β-amyloid plaques identified by standard neuropathological techniques and correlated with the density of Aβ measured by immunohistochemistry. Since β-amyloid plaques are a defining neuropathological feature for Alzheimer’s disease, these results support the use of florbetapir F 18 as an amyloid PET ligand to identify the presence of AD pathology in patients with signs and symptoms of progressive late-life cognitive impairment.
PMCID: PMC3286131  PMID: 22354138
PET imaging; Alzheimer’s disease; β-amyloid plaque; autoradiography; β-amyloid; amyloid PET imaging; florbetapir F 18; 18F-AV-45; postmortem
2.  Florbetapir PET analysis of amyloid-β deposition in the presenilin 1 E280A autosomal dominant Alzheimer’s disease kindred: a cross-sectional study 
Lancet neurology  2012;11(12):10.1016/S1474-4422(12)70227-2.
Fibrillar amyloid-β (Aβ) is thought to begin accumulating in the brain many years before the onset of clinical impairment in patients with Alzheimer’s disease. By assessing the accumulation of Aβ in people at risk of genetic forms of Alzheimer’s disease, we can identify how early preclinical changes start in individuals certain to develop dementia later in life. We sought to characterise the age-related accumulation of Aβ deposition in presenilin 1 (PSEN1) E280A mutation carriers across the spectrum of preclinical disease.
Between Aug 1 and Dec 6, 2011, members of the familial Alzheimer’s disease Colombian kindred aged 18–60 years were recruited from the Alzheimer’s Prevention Initiative’s registry at the University of Antioquia, Medellín, Colombia. Cross-sectional assessment using florbetapir PET was done in symptomatic mutation carriers with mild cognitive impairment or mild dementia, asymptomatic carriers, and asymptomatic non-carriers. These assessments were done at the Banner Alzheimer’s Institute in Phoenix, AZ, USA. A cortical grey matter mask consisting of six predefined regions. was used to measure mean cortical florbetapir PET binding. Cortical-to-pontine standard-uptake value ratios were used to characterise the cross-sectional accumulation of fibrillar Aβ deposition in carriers and non-carriers with regression analysis and to estimate the trajectories of fibrillar Aβ deposition.
We enrolled a cohort of 11 symptomatic individuals, 19 presymptomatic mutation carriers, and 20 asymptomatic non-carriers, ranging in age from 20 to 56 years. There was greater florbetapir binding in asymptomatic PSEN1 E280A mutation carriers than in age matched non-carriers. Fibrillar Aβ began to accumulate in PSEN 1E280A mutation carriers at a mean age of 28·2 years (95% CI 27·3–33·4), about 16 years and 21 years before the predicted median ages at mild cognitive impairment and dementia onset, respectively. 18F florbetapir binding rose steeply over the next 9·4 years and plateaued at a mean age of 37·6 years (95% CI 35·3–40·2), about 6 and 11 years before the expected respective median ages at mild cognitive impairment and dementia onset. Prominent florbetapir binding was seen in the anterior and posterior cingulate, precuneus, and parietotemporal and frontal grey matter, as well as in the basal ganglia. Binding in the basal ganglia was not seen earlier or more prominently than in other regions.
These findings contribute to the understanding of preclinical familial Alzheimer’s disease and help set the stage for assessment of amyloid-modifying treatments in the prevention of familial Alzheimer’s disease.
Avid Radiopharmaceuticals, Banner Alzheimer’s Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Colciencias, National Institute on Aging, and the State of Arizona.
PMCID: PMC3515078  PMID: 23137949
3.  Tauopathy PET and amyloid PET in the diagnosis of chronic traumatic encephalopathies: studies of a retired NFL player and of a man with FTD and a severe head injury 
Translational Psychiatry  2014;4(9):e441-.
Single, severe traumatic brain injury (TBI) which elevates CNS amyloid, increases the risk of Alzheimer's disease (AD); while repetitive concussive and subconcussive events as observed in athletes and military personnel, may increase the risk of chronic traumatic encephalopathy (CTE). We describe two clinical cases, one with a history of multiple concussions during a career in the National Football League (NFL) and the second with frontotemporal dementia and a single, severe TBI. Both patients presented with cognitive decline and underwent [18F]-Florbetapir positron emission tomography (PET) imaging for amyloid plaques; the retired NFL player also underwent [18F]-T807 PET imaging, a new ligand binding to tau, the main constituent of neurofibrillary tangles (NFT). Case 1, the former NFL player, was 71 years old when he presented with memory impairment and a clinical profile highly similar to AD. [18F]-Florbetapir PET imaging was negative, essentially excluding AD as a diagnosis. CTE was suspected clinically, and [18F]-T807 PET imaging revealed striatal and nigral [18F]-T807 retention consistent with the presence of tauopathy. Case 2 was a 56-year-old man with personality changes and cognitive decline who had sustained a fall complicated by a subdural hematoma. At 1 year post injury, [18F]-Florbetapir PET imaging was negative for an AD pattern of amyloid accumulation in this subject. Focal [18F]-Florbetapir retention was noted at the site of impact. In case 1, amyloid imaging provided improved diagnostic accuracy where standard clinical and laboratory criteria were inadequate. In that same case, tau imaging with [18F]-T807 revealed a subcortical tauopathy that we interpret as a novel form of CTE with a distribution of tauopathy that mimics, to some extent, that of progressive supranuclear palsy (PSP), despite a clinical presentation of amnesia without any movement disorder complaints or signs. A key distinguishing feature is that our patient presented with hippocampal involvement, which is more frequently seen in CTE than in PSP. In case 2, focal [18F]-Florbetapir retention at the site of injury in an otherwise negative scan suggests focal amyloid aggregation. In each of these complex cases, a combination of [18F]-fluorodeoxyglucose, [18F]-Florbetapir and/or [18F]-T807 PET molecular imaging improved the accuracy of diagnosis and prevented inappropriate interventions.
PMCID: PMC4203018  PMID: 25226550
4.  A consecutive case series experience with [18 F] florbetapir PET imaging in an urban dementia center: impact on quality of life, decision making, and disposition 
Identification and quantification of fibrillar amyloid in brain using positron emission tomography (PET) imaging and Amyvid™ ([18 F] Amyvid, [18 F] florbetapir, 18 F-AV-45) was recently approved by the US Food and Drug Administration as a clinical tool to estimate brain amyloid burden in patients being evaluated for cognitive impairment or dementia. Imaging with [18 F] florbetapir offers in vivo confirmation of the presence of cerebral amyloidosis and may increase the accuracy of the diagnosis and likely cause of cognitive impairment (CI) or dementia. Most importantly, amyloid imaging may improve certainty of etiology in situations where the differential diagnosis cannot be resolved on the basis of standard clinical and laboratory criteria.
A consecutive case series of 30 patients (age 50-89; 16 M/14 F) were clinically evaluated at a cognitive evaluation center of urban dementia center and referred for [18 F] florbetapir PET imaging as part of a comprehensive dementia workup. Evaluation included neurological examination and neuropsychological assessment by dementia experts. [18 F] florbetapir PET scans were read by trained nuclear medicine physicians using the qualitative binary approach. Scans were rated as either positive or negative for the presence of cerebral amyloidosis. In addition to a comprehensive dementia evaluation, post [18 F] florbetapir PET imaging results caused diagnoses to be changed in 10 patients and clarified in 9 patients. Four patients presenting with SCI were negative for amyloidosis. These results show that [18 F] florbetapir PET imaging added diagnostic clarification and discrimination in over half of the patients evaluated.
Amyloid imaging provided novel and essential data that: (1) caused diagnosis to be revised; and/or (2) prevented the initiation of incorrect or suboptimal treatment; and/or (3) avoided inappropriate referral to an anti-amyloid clinical trial.
PMCID: PMC3913628  PMID: 24484858
Amyvid™; Florbetapir; PET; Clinical series; Alzheimer’s disease; Neuroimaging
5.  Neuropathologic Heterogeneity Does Not Impair Florbetapir-PET Postmortem Correlates 
Neuropathologic heterogeneity is often present within Alzheimer’s disease (AD). We sought to determine if amyloid imaging measures of AD are affected by concurrent pathologies. Thirty-eight clinicopathologically-defined AD and 17 non-demented cases (ND) with quantitative florbetapir F-18 (18F-AV-45) PET imaging during life and histological β-amyloid quantification and neuropathologic examination were assessed. AD cases were divided on the basis of concurrent pathologies, including those with Lewy bodies (N=21), white matter rarefaction (N=27), severe cerebral amyloid angiopathy (N=11), argyrophilic grains (N=5) and TDP-43 inclusions (N=18). Many cases exhibited more than one type of concurrent pathology. The ratio of cortical to cerebellar amyloid imaging signal (SUVr) and immunohistochemical β-amyloid load were analyzed in six cortical regions of interest. All AD subgroups had strong and significant correlations between SUVr and histological β-amyloid measures (p values <0.001). All AD subgroups had significantly greater amyloid measures compared to ND, and mean amyloid measures did not significantly differ between AD subgroups. When comparing AD cases with and without each pathology, AD cases with Lewy bodies had significantly decreased SUVr measures compared to AD cases without (p = 0.002); there were no other paired comparison differences. These findings indicate florbetapir-PET imaging is not confounded by neuropathological heterogeneity within AD.
PMCID: PMC4037918  PMID: 24335535
argyrophilic grains; autopsy; cerebral amyloid angiopathy; Lewy bodies; plaques; TDP-43; vascular dementia; white matter; leuko-araiosis
6.  Amyloid Deposition, Hypometabolism, and Longitudinal Cognitive Decline 
Annals of neurology  2012;72(4):578-586.
Using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) population, we examined (1) cross-sectional relationships between amyloid deposition, hypometabolism, and cognition, and (2) associations between amyloid and hypometabolism measurements and longitudinal cognitive measurements.
We examined associations between mean cortical florbetapir uptake, mean 18F-fluorodeoxyglucose–positron emission tomography (FDG-PET) within a set of predefined regions, and Alzhiemer’s Disease Assessment Scale (ADAS-cog) performance in 426 ADNI participants (126 normal, 162 early mild cognitive impairment [EMCI], 85 late MCI [LMCI], 53 Alzheimer disease [AD] patients). For a subset of these (76 normal, 81 LMCI) we determined whether florbetapir and FDG-PET were associated with retrospective decline in longitudinal ADAS-cog measurements.
Twenty-nine percent of normal subjects, 43% of EMCI patients, 62% of LMCI patients, and 77% of AD patients were categorized as florbetapir positive. Florbetapir was negatively associated with concurrent FDG and ADAS-cog in both MCI groups. In longitudinal analyses, florbetapir-positive subjects in both normal and LMCI groups had greater ongoing ADAS-cog decline than those who were florbetapir negative. However, in normal subjects, florbetapir positivity was associated with greater ADAS-cog decline than FDG, whereas in LMCI, FDG positivity was associated with greater decline than florbetapir.
Although both hypometabolism and β-amyloid (Aβ) deposition are detectable in normal subjects and all diagnostic groups, Aβ showed greater associations with cognitive decline in normal participants. In view of the minimal cognitive deterioration overall in this group, this suggests that amyloid deposition has an early and subclinical impact on cognition that precedes metabolic changes. At moderate and later stages of disease (LMCI/AD), hypometabolism becomes more pronounced and more closely linked to ongoing cognitive decline.
PMCID: PMC3786871  PMID: 23109153
7.  Resorufin analogs preferentially bind cerebrovascular amyloid: potential use as imaging ligands for cerebral amyloid angiopathy 
Cerebral amyloid angiopathy (CAA) is characterized by deposition of fibrillar amyloid β (Aβ) within cerebral vessels. It is commonly seen in the elderly and almost universally present in patients with Alzheimer's Disease (AD). In both patient populations, CAA is an independent risk factor for lobar hemorrhage, ischemic stroke, and dementia. To date, definitive diagnosis of CAA requires obtaining pathological tissues via brain biopsy (which is rarely clinically indicated) or at autopsy. Though amyloid tracers labeled with positron-emitting radioligands such as [11C]PIB have shown promise for non-invasive amyloid imaging in AD patients, to date they have been unable to clarify whether the observed amyloid load represents neuritic plaques versus CAA due in large part to the low resolution of PET imaging and the almost equal affinity of these tracers for both vascular and parenchymal amyloid. Therefore, the development of a precise and specific non-invasive technique for diagnosing CAA in live patients is desired.
We found that the phenoxazine derivative resorufin preferentially bound cerebrovascular amyloid deposits over neuritic plaques in the aged Tg2576 transgenic mouse model of AD/CAA, whereas the congophilic amyloid dye methoxy-X34 bound both cerebrovascular amyloid deposits and neuritic plaques. Similarly, resorufin-positive staining was predominantly noted in fibrillar Aβ-laden vessels in postmortem AD brain tissues. Fluorescent labeling and multi-photon microscopy further revealed that both resorufin- and methoxy-X34-positive staining is colocalized to the vascular smooth muscle (VSMC) layer of vessel segments that have severe disruption of VSMC arrangement, a characteristic feature of CAA. Resorufin also selectively visualized vascular amyloid deposits in live Tg2576 mice when administered topically, though not systemically. Resorufin derivatives with chemical modification at the 7-OH position of resorufin also displayed a marked preferential binding affinity for CAA, but with enhanced lipid solubility that indicates their use as a non-invasive imaging tracer for CAA is feasible.
To our knowledge, resorufin analogs are the fist class of amyloid dye that can discriminate between cerebrovascular and neuritic forms of amyloid. This unique binding selectivity suggests that this class of dye has great potential as a CAA-specific amyloid tracer that will permit non-invasive detection and quantification of CAA in live patients.
PMCID: PMC3259047  PMID: 22192811
Cerebral amyloid angiopathy; Alzheimer's disease; dementia; diagnosis; amyloid beta; positron emission tomography; amyloid imaging; tracer; resorufin; phenoxazines
8.  Positron emission tomography imaging and clinical progression in relation to molecular pathology in the first Pittsburgh Compound B positron emission tomography patient with Alzheimer’s disease 
Brain  2010;134(1):301-317.
The accumulation of β-amyloid in the brain is an early event in Alzheimer’s disease. This study presents the first patient with Alzheimer’s disease who underwent positron emission tomography imaging with the amyloid tracer, Pittsburgh Compound B to visualize fibrillar β-amyloid in the brain. Here we relate the clinical progression, amyloid and functional brain positron emission tomography imaging with molecular neuropathological alterations at autopsy to gain new insight into the relationship between β-amyloid accumulation, inflammatory processes and the cholinergic neurotransmitter system in Alzheimer’s disease brain. The patient underwent positron emission tomography studies with 18F-fluorodeoxyglucose three times (at ages 53, 56 and 58 years) and twice with Pittsburgh Compound B (at ages 56 and 58 years), prior to death at 61 years of age. The patient showed a pronounced decline in cerebral glucose metabolism and cognition during disease progression, while Pittsburgh Compound B retention remained high and stable at follow-up. Neuropathological examination of the brain at autopsy confirmed the clinical diagnosis of pure Alzheimer’s disease. A comprehensive neuropathological investigation was performed in nine brain regions to measure the regional distribution of β-amyloid, neurofibrillary tangles and the levels of binding of 3H-nicotine and 125I-α-bungarotoxin to neuronal nicotinic acetylcholine receptor subtypes, 3H-L-deprenyl to activated astrocytes and 3H-PK11195 to microglia, as well as butyrylcholinesterase activity. Regional in vivo 11C-Pittsburgh Compound B-positron emission tomography retention positively correlated with 3H-Pittsburgh Compound B binding, total insoluble β-amyloid, and β-amyloid plaque distribution, but not with the number of neurofibrillary tangles measured at autopsy. There was a negative correlation between regional fibrillar β-amyloid and levels of 3H-nicotine binding. In addition, a positive correlation was found between regional 11C-Pittsburgh Compound B positron emission tomography retention and 3H-Pittsburgh Compound B binding with the number of glial fibrillary acidic protein immunoreactive cells, but not with 3H-L-deprenyl and 3H-PK-11195 binding. In summary, high 11C-Pittsburgh Compound B positron emission tomography retention significantly correlates with both fibrillar β-amyloid and losses of neuronal nicotinic acetylcholine receptor subtypes at autopsy, suggesting a closer involvement of β-amyloid pathology with neuronal nicotinic acetylcholine receptor subtypes than with inflammatory processes.
PMCID: PMC3009843  PMID: 21149866
Alzheimer’s disease; autopsy brain; 11C-PIB positron emission tomography; inflammation; nicotinic acetylcholine receptors
9.  Genetic Susceptibility for Alzheimer’s Disease Neuritic Plaque Pathology 
JAMA neurology  2013;70(9):1150-1157.
To investigate whether Alzheimer’s disease (AD) susceptibility loci from genome-wide association studies (GWAS) impact neuritic plaque pathology and to additionally identify novel risk loci for this trait.
Candidate analysis of single nucleotide polymorphisms (SNPs) and GWAS in a joint clinicopathologic cohort study, followed by targeted validation in independent neuroimaging cohorts.
Participants and Setting
725 deceased subjects from the Religious Orders and Rush Memory and Aging Project, two prospective, community-based studies of aging; the validation neuroimaging cohort consisted of 114 subjects from multiple clinical and research centers.
Main Outcome Measures
A quantitative measure of neuritic plaque pathologic burden, based on assessments of silver-stained tissue averaged from multiple brain regions. Validation based on β-amyloid load by immunocytochemistry, and replication with fibrillar β-amyloid Positron Emission Tomography (PET) imaging with Pittsburgh Compound B or florbetapir.
Besides the previously reported APOE and CR1 loci, we find that ABCA7 (rs3764650, P=0.02) and CD2AP (rs9349407, P=0.03) AD susceptibility loci are associated with neuritic plaque burden. In addition, among the top results of our GWAS, we discovered a novel variant near the amyloid precursor protein gene (APP, rs2829887) that is associated with neuritic plaques (P=3.3×10−6). This polymorphism was associated with postmortem β-amyloid load, as well as fibrillar β-amyloid in two independent cohorts of adults with normal cognition.
These findings enhance understanding of AD risk factors by relating validated susceptibility alleles to increased neuritic plaque pathology and implicate common genetic variation at the APP locus in the earliest, pre-symptomatic stages of AD.
PMCID: PMC3773291  PMID: 23836404
10.  Amyloid-β Imaging with Pittsburgh Compound B and Florbetapir: Comparing Radiotracers and Quantification Methods 
11C-Pittsburgh compound B (11C-PiB) and 18F-florbetapir amyloid-β (Aβ) PET radioligands have had a substantial impact on Alzheimer disease research. Although there is evidence that both radioligands bind to fibrillar Aβ in the brain, direct comparisons in the same individuals have not been reported. Here, we evaluated PiB and florbetapir in a retrospective convenience sample of cognitively normal older controls, patients with mild cognitive impairment, and patients with Alzheimer disease from the Alzheimer’s Disease Neuroimaging Initiative (ADNI).
From the ADNI database, 32 participants were identified who had undergone at least 1 PiB study and subsequently underwent a florbetapir study approximately 1.5 y after the last PiB study. Cortical PiB and florbetapir retention was quantified using several different methods to determine the effect of preprocessing factors (such as smoothing and reference region selection) and image processing pipelines.
There was a strong association between PiB and florbetapir cortical retention ratios (Spearman ρ = 0.86–0.95), and these were slightly lower than cortical retention ratios for consecutive PiB scans (Spearman ρ = 0.96–0.98) made approximately 1.1 y apart. Cortical retention ratios for Aβ-positive subjects tended to be higher for PiB than for florbetapir images, yielding slopes for linear regression of florbetapir against PiB of 0.59–0.64. Associations between consecutive PiB scans and between PiB and florbetapir scans remained strong, regardless of processing methods such as smoothing, spatial normalization to a PET template, and use of reference regions. The PiB–florbetapir association was used to interconvert cutoffs for Aβ positivity and negativity between the 2 radioligands, and these cutoffs were highly consistent in their assignment of Aβ status.
PiB and florbetapir retention ratios were strongly associated in the same individuals, and this relationship was consistent across several data analysis methods, despite scan–rescan intervals of more than a year. Cutoff thresholds for determining positive or negative Aβ status can be reliably transformed from PiB to florbetapir units or vice versa using a population scanned with both radioligands.
PMCID: PMC3747730  PMID: 23166389
amyloid-β; Alzheimer’s disease; PET imaging
11.  In vivo amyloid imaging in autopsy-confirmed Parkinson disease with dementia 
Neurology  2010;74(1):77-84.
To investigate the specificity of in vivo amyloid imaging with [11C]–Pittsburgh Compound B (PIB) in Parkinson disease dementia (PDD).
We performed detailed neuropathologic examination for 3 individuals with PDD who had PIB PET imaging within 15 months of death.
We observed elevated cortical uptake of [11C]-PIB on in vivo PET imaging in 2 of the 3 cases. At autopsy, all 3 individuals had abundant cortical Lewy bodies (Braak PD stage 6), and were classified as low-probability Alzheimer disease (AD) based on NIA-Reagan criteria. The 2 PIB-positive individuals had abundant diffuse Aβ plaques but only sparse neuritic plaques and intermediate neurofibrillary tangle pathology. The PIB-negative individual had rare diffuse plaques, no neuritic plaques, and low neurofibrillary tangle burden.
[11C]–Pittsburgh Compound B (PIB) PET is specific for fibrillar Aβ molecular pathology but not for pathologic diagnosis of comorbid Alzheimer disease in individuals with Parkinson disease dementia. The ability to specifically identify fibrillar Aβ amyloid in the setting of α-synucleinopathy makes [11C]-PIB PET a valuable tool for prospectively evaluating how the presence of Aβ amyloid influences the clinical course of dementia in patients with Lewy body disorders.
= Alzheimer disease;
= binding potentials;
= Clinical Dementia Rating;
= dementia of the Alzheimer type;
= dementia with Lewy bodies;
= distribution volume;
= Mental State Examination;
= Neuropsychiatric Inventory Questionnaire;
= Parkinson disease dementia;
= Pittsburgh Compound B;
= Unified Parkinson's Disease Rating Scale.
PMCID: PMC2809026  PMID: 20038776
12.  Absence of PIttsburgh Compound B Detection of CerebralAmyloid Beta in a Patient With Clinical, Cognitive, and Cerebrospinal FluidMarkers of Alzheimer Disease 
Archives of neurology  2009;66(12):1557-1562.
To determine the temporal relationships of clinical, cognitive, Pittsburgh Compound-B (PiB) amyloid imaging, and cerebrospinal fluid (CSF) markers of Alzheimer’s disease (AD).
A case report of a longitudinally assessed participant in a memory and aging study who had serial clinical and psychometric assessments over 6 years, in addition to PiB imaging and CSF biomarker assays, prior to coming to autopsy.
Alzheimer’s Disease Research Center
An 85-year old individual was cognitively normal at his initial and next 3 annual assessments. Decline in measures of episodic memory and, to a lesser degree, working memory began at about age 88 years. PiB-PET amyloid imaging was negative at age 88.5 years, but at age 89.5 years there was reduced amyloid-beta 42 (Aβ42) and elevated levels of tau in the CSF. At his 6th assessment, when he was 90 years old, he was diagnosed with very mild dementia of the Alzheimer type. After death at age 91 years, the autopsy revealed foci of frequent neocortical diffuse Aβ plaques, sufficient to fulfill Khachaturian neuropathologic criteria for AD, but neuritic plaques and neurofibrillary tangles were sparse. Postmortem biochemical analysis of the cerebral tissue confirmed that PiB-PET-binding was below the level needed for in vivo detection.
Clinical, cognitive, and CSF markers consistent with AD may precede detection of cerebral Aβ with amyloid imaging agents such as PiB, which primarily label fibrillar Aβ plaques.
PMCID: PMC2796200  PMID: 20008664
13.  β-Amyloid is associated with aberrant metabolic connectivity in subjects with mild cognitive impairment 
Positron emission tomography (PET) studies using [18F]2-fluoro-2-deoxyglucose (FDG) have identified a well-defined pattern of glucose hypometabolism in Alzheimer's disease (AD). The assessment of the metabolic relationship among brain regions has the potential to provide unique information regarding the disease process. Previous studies of metabolic correlation patterns have demonstrated alterations in AD subjects relative to age-matched, healthy control subjects. The objective of this study was to examine the associations between β-amyloid, apolipoprotein E ɛ4 (APOE ɛ4) genotype, and metabolic correlations patterns in subjects diagnosed with mild cognitive impairment (MCI). Mild cognitive impairment subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study were categorized into β-amyloid-low and β-amyloid-high groups, based on quantitative analysis of [18F]florbetapir PET scans, and APOE ɛ4 non-carriers and carriers based on genotyping. We generated voxel-wise metabolic correlation strength maps across the entire cerebral cortex for each group, and, subsequently, performed a seed-based analysis. We found that the APOE ɛ4 genotype was closely related to regional glucose hypometabolism, while elevated, fibrillar β-amyloid burden was associated with specific derangements of the metabolic correlation patterns.
PMCID: PMC4083380  PMID: 24736891
APOE ɛ4; β-amyloid; FDG PET; florbetapir PET; metabolic connectivity; mild cognitive impairment
14.  Diagnostic accuracy of CSF Ab42 and florbetapir PET for Alzheimer's disease 
Reduced cerebrospinal fluid (CSF) β-amyloid42 (Aβ42) and increased florbetapir positron emission tomography (PET) uptake reflects brain Aβ accumulation. These biomarkers are correlated with each other and altered in Alzheimer's disease (AD), but no study has directly compared their diagnostic performance.
We examined healthy controls (CN, N = 169) versus AD dementia patients (N = 118), and stable (sMCI; no dementia, followed up for at least 2 years, N = 165) versus progressive MCI (pMCI; conversion to AD dementia, N = 59). All subjects had florbetapir PET (global and regional; temporal, frontal, parietal, and cingulate) and CSF Aβ42 measurements at baseline. We compared area under the curve (AUC), sensitivity, and specificity (testing a priori and optimized cutoffs). Clinical diagnosis was the reference standard.
CSF Aβ42 and (global or regional) PET florbetapir did not differ in AUC (CN vs. AD, CSF 84.4%; global PET 86.9%; difference [95% confidence interval] −6.7 to 1.5). CSF Aβ42 and global PET florbetapir did not differ in sensitivity, but PET had greater specificity than CSF in most comparisons. Sixteen CN progressed to MCI and AD (six Aβ negative, seven Aβ positive, and three PET positive but CSF negative).
The overall diagnostic accuracies of CSF Aβ42 and PET florbetapir were similar, but PET had greater specificity. This was because some CN and sMCI subjects appear pathological using CSF but not using PET, suggesting that low CSF Aβ42 not always translates to cognitive decline or brain Aβ accumulation. Other factors, including costs and side effects, may also be considered when determining the optimal modality for different applications.
PMCID: PMC4184556  PMID: 25356425
15.  Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease 
Brain  2008;131(6):1630-1645.
The positron emission tomography (PET) radiotracer Pittsburgh Compound-B (PiB) binds with high affinity to β-pleated sheet aggregates of the amyloid-β (Aβ) peptide in vitro. The in vivo retention of PiB in brains of people with Alzheimer's disease shows a regional distribution that is very similar to distribution of Aβ deposits observed post-mortem. However, the basis for regional variations in PiB binding in vivo, and the extent to which it binds to different types of Aβ-containing plaques and tau-containing neurofibrillary tangles (NFT), has not been thoroughly investigated. The present study examined 28 clinically diagnosed and autopsy-confirmed Alzheimer's disease subjects, including one Alzheimer's disease subject who had undergone PiB-PET imaging 10 months prior to death, to evaluate region- and substrate-specific binding of the highly fluorescent PiB derivative 6-CN-PiB. These data were then correlated with region-matched Aβ plaque load and peptide levels, [3H]PiB binding in vitro, and in vivo PET retention levels. We found that in Alzheimer's disease brain tissue sections, the preponderance of 6-CN-PiB binding is in plaques immunoreactive to either Aβ42 or Aβ40, and to vascular Aβ deposits. 6-CN-PiB labelling was most robust in compact/cored plaques in the prefrontal and temporal cortices. While diffuse plaques, including those in caudate nucleus and presubiculum, were less prominently labelled, amorphous Aβ plaques in the cerebellum were not detectable with 6-CN-PiB. Only a small subset of NFT were 6-CN-PiB positive; these resembled extracellular ‘ghost’ NFT. In Alzheimer's disease brain tissue homogenates, there was a direct correlation between [3H]PiB binding and insoluble Aβ peptide levels. In the Alzheimer's disease subject who underwent PiB-PET prior to death, in vivo PiB retention levels correlated directly with region-matched post-mortem measures of [3H]PiB binding, insoluble Aβ peptide levels, 6-CN-PiB- and Aβ plaque load, but not with measures of NFT. These results demonstrate, in a typical Alzheimer's disease brain, that PiB binding is highly selective for insoluble (fibrillar) Aβ deposits, and not for neurofibrillary pathology. The strong direct correlation of in vivo PiB retention with region-matched quantitative analyses of Aβ plaques in the same subject supports the validity of PiB-PET imaging as a method for in vivo evaluation of Aβ plaque burden.
PMCID: PMC2408940  PMID: 18339640
Pittsburgh Compound-B; PiB; amyloid imaging; plaques; PET imaging
16.  Apolipoprotein E, not Fibrillar β-amyloid, Reduces Cerebral Glucose Metabolism in Normal Aging 
The ε4 allele of the polymorphic apolipoprotein E gene is associated with increased risk of Alzheimer's disease (AD), deposition of β-amyloid (Aβ), and reduction in cerebral glucose metabolism in asymptomatic people. Although ApoE4 may exert an effect on AD risk through amyloidogenic pathways, whether its effect on glucose metabolism is related to Aβ is unknown. To answer this question, we examined data from 175 cognitively normal older people (mean age 77, 87 men, 88 women) in the Alzheimer's disease neuroimaging initiative studied concurrently with [18F]Flurodeoxyglucose (FDG) PET measures of glucose metabolism and the radiotracer [18F]florbetapir, an imaging agent which labels fibrillar Aβ in vivo. Based on a threshold value of florbetapir uptake determined in separate samples, subjects were categorized as florbetapir+ or florbetapir-. Glucose metabolism was measured as a continuous variable in a group of regions of interest (ROIs) selected a priori based on their involvement in AD, and also using a whole-brain voxelwise approach. Amongst this sample, 29% of subjects were florbetapir+, and 23% were ApoE4 carriers. As expected, there was a significant association between ApoE4 genotype and florbetapir positivity. Florbetapir status, however, was not significantly associated with glucose metabolism, but the ApoE4 genotype was associated with lower metabolism in both voxelwise and ROI approaches. These results show that ApoE genotype, and not aggregated fibrillar forms of Aβ, contributes to reduced glucose metabolism in aging and add to a growing list of neural consequences of ApoE that do not appear to be related to Aβ.
PMCID: PMC3537830  PMID: 23238736
17.  Amyloid-β assessed by florbetapir F 18 PET and 18-month cognitive decline 
Neurology  2012;79(16):1636-1644.
Florbetapir F 18 PET can image amyloid-β (Aβ) aggregates in the brains of living subjects. We prospectively evaluated the prognostic utility of detecting Aβ pathology using florbetapir PET in subjects at risk for progressive cognitive decline.
A total of 151 subjects who previously participated in a multicenter florbetapir PET imaging study were recruited for longitudinal assessment. Subjects included 51 with recently diagnosed mild cognitive impairment (MCI), 69 cognitively normal controls (CN), and 31 with clinically diagnosed Alzheimer disease dementia (AD). PET images were visually scored as positive (Aβ+) or negative (Aβ−) for pathologic levels of β-amyloid aggregation, blind to diagnostic classification. Cerebral to cerebellar standardized uptake value ratios (SUVr) were determined from the baseline PET images. Subjects were followed for 18 months to evaluate changes in cognition and diagnostic status. Analysis of covariance and correlation analyses were conducted to evaluate the association between baseline PET amyloid status and subsequent cognitive decline.
In both MCI and CN, baseline Aβ+ scans were associated with greater clinical worsening on the Alzheimer's Disease Assessment Scale–Cognitive subscale (ADAS-Cog (p < 0.01) and Clinical Dementia Rating–sum of boxes (CDR-SB) (p < 0.02). In MCI Aβ+ scans were also associated with greater decline in memory, Digit Symbol Substitution (DSS), and Mini-Mental State Examination (MMSE) (p < 0.05). In MCI, higher baseline SUVr similarly correlated with greater subsequent decline on the ADAS-Cog (p < 0.01), CDR-SB (p < 0.03), a memory measure, DSS, and MMSE (p < 0.05). Aβ+ MCI tended to convert to AD dementia at a higher rate than Aβ− subjects (p < 0.10).
Florbetapir PET may help identify individuals at increased risk for progressive cognitive decline.
PMCID: PMC3468774  PMID: 22786606
18.  Using PET with 18F-AV-45 (florbetapir) to quantify brain amyloid load in a clinical environment 
Positron emission tomography (PET) imaging of brain amyloid load has been suggested as a core biomarker for Alzheimer’s disease (AD). The aim of this study was to test the feasibility of using PET imaging with 18F-AV-45 (florbetapir) in a routine clinical environment to differentiate between patients with mild to moderate AD and mild cognitive impairment (MCI) from normal healthy controls (HC).
In this study, 46 subjects (20 men and 26 women, mean age of 69.0 ± 7.6 years), including 13 with AD, 12 with MCI and 21 HC subjects, were enrolled from three academic memory clinics. PET images were acquired over a 10-min period 50 min after injection of florbetapir (mean ± SD of radioactivity injected, 259 ± 57 MBq). PET images were assessed visually by two individuals blinded to any clinical information and quantitatively via the standard uptake value ratio (SUVr) in the specific regions of interest, which were defined in relation to the cerebellum as the reference region.
The mean values of SUVr were higher in AD patients (median 1.20, Q1-Q3 1.16-1.30) than in HC subjects (median 1.05, Q1-Q3 1.04-1.08; p = 0.0001) in the overall cortex and all cortical regions (precuneus, anterior and posterior cingulate, and frontal median, temporal, parietal and occipital cortex). The MCI subjects also showed a higher uptake of florbetapir in the posterior cingulate cortex (median 1.06, Q1-Q3 0.97-1.28) compared with HC subjects (median 0.95, Q1-Q3 0.82-1.02; p = 0.03). Qualitative visual assessment of the PET scans showed a sensitivity of 84.6% (95% CI 0.55–0.98) and a specificity of 38.1% (95% CI 0.18–0.62) for discriminating AD patients from HC subjects; however, the quantitative assessment of the global cortex SUVr showed a sensitivity of 92.3% and specificity of 90.5% with a cut-off value of 1.122 (area under the curve 0.894).
These preliminary results suggest that PET with florbetapir is a safe and suitable biomarker for AD that can be used routinely in a clinical environment. However, the low specificity of the visual PET scan assessment could be improved by the use of specific training and automatic or semiautomatic quantification tools.
PMCID: PMC3315642  PMID: 22252372
18F-AV-45; Florbetapir; Alzheimer’s disease; PET imaging; Brain imaging
19.  Imaging amyloid deposition in Lewy body diseases 
Neurology  2008;71(12):903-910.
Extrapyramidal motor symptoms precede dementia in Parkinson disease (PDD) by many years, whereas dementia occurs early in dementia with Lewy bodies (DLB). Despite this clinical distinction, the neuropsychological and neuropathologic features of these conditions overlap. In addition to widespread distribution of Lewy bodies, both diseases have variable burdens of neuritic plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD).
To determine whether amyloid deposition, as assessed by PET imaging with the β-amyloid–binding compound Pittsburgh Compound B (PiB), can distinguish DLB from PDD, and to assess whether regional patterns of amyloid deposition correlate with specific motor or cognitive features.
Eight DLB, 7 PDD, 11 Parkinson disease (PD), 15 AD, and 37 normal control (NC) subjects underwent PiB-PET imaging and neuropsychological assessment. Amyloid burden was quantified using the PiB distribution volume ratio.
Cortical amyloid burden was higher in the DLB group than in the PDD group, comparable to the AD group. Amyloid deposition in the PDD group was low, comparable to the PD and NC groups. Relative to global cortical retention, occipital PiB retention was lower in the AD group than in the other groups. For the DLB, PDD, and PD groups, amyloid deposition in the parietal (lateral and precuneus)/posterior cingulate region was related to visuospatial impairment. Striatal PiB retention in the DLB and PDD groups was associated with less impaired motor function.
Global cortical amyloid burden is high in dementia with Lewy bodies (DLB) but low in Parkinson disease dementia. These data suggest that β-amyloid may contribute selectively to the cognitive impairment of DLB and may contribute to the timing of dementia relative to the motor signs of parkinsonism.
= Automated Anatomic Labeling;
= Alzheimer disease;
= Alzheimer’s Disease Research Center;
= American version of the National Adult Reading Test;
= analysis of covariance;
= Blessed Dementia Scale;
= cerebral amyloid angiopathy;
= Clinical Dementia Rating;
= Clinical Dementia Rating Sum of Boxes;
= dementia with Lewy bodies;
= distribution volume ratio;
= Cued Selective Reminding Test;
= Free Selective Reminding Test;
= Hoehn and Yahr;
= Massachusetts General Hospital;
= Mini-Mental State Examination;
= normal control;
= neurofibrillary tangle;
= Neuropsychiatric Inventory Questionnaire;
= not significant;
= Parkinson disease;
= Parkinson disease dementia;
= Pittsburgh Compound B;
= region of interest;
= Statistical Parametric Mapping;
= UK Parkinson’s Disease Society Brain Bank Research Center;
= United Parkinson’s Disease Rating Scale;
= Wechsler Adult Intelligence Scale–Revised.
PMCID: PMC2637553  PMID: 18794492
20.  Positive Florbetapir PET Amyloid Imaging in a Subject with Frequent Cortical Neuritic Plaques and Frontotemporal Lobar Degeneration with TDP43-Positive Inclusions 
Abnormal neuronal accumulation and modification of TAR DNA binding protein 43 (TDP-43) have recently been discovered to be defining histopathological features of particular subtypes of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), and are also common in aging, particularly coexisting with hippocampal sclerosis and Alzheimer's disease (AD) pathology. This case report describes a 72 year old Hispanic male with no family history of neurological disease, who presented at age 59 with obsessive behavior, anxiety, agitation and dysphasia. Positron emission tomography (PET) imaging using the amyloid ligand 18F florbetapir (Amyvid) was positive. Postmortem examination revealed frequent diffuse and neuritic amyloid plaques throughout the cerebral cortex, thalamus and striatum, Braak stage II neurofibrillary degeneration and frequent frontal and temporal cortex TDP-43-positive neurites with rare nuclear inclusions. The case is unusual and instructive because of the co-existence of frequent cortical and diencephalic amyloid plaques with extensive TDP-43-positive histopathology in the setting of early-onset dementia and because it demonstrates that a positive cortical amyloid imaging signal in a subject with dementia does not necessarily establish that AD is the sole cause.
PMCID: PMC4167919  PMID: 24927705
Alzheimer's disease; frontotemporal dementia; neurofibrillary degeneration; neuritic amyloid plaques
21.  Induction of complement proteins in a mouse model for cerebral microvascular Aβ deposition 
The deposition of amyloid β-protein (Aβ) in cerebral vasculature, known as cerebral amyloid angiopathy (CAA), is a common pathological feature of Alzheimer's disease and related disorders. In familial forms of CAA single mutations in the Aβ peptide have been linked to the increase of vascular Aβ deposits accompanied by a strong localized activation of glial cells and elevated expression of neuroinflammatory mediators including complement proteins. We have developed human amyloid-β precursor protein transgenic mice harboring two CAA Aβ mutations (Dutch E693Q and Iowa D694N) that mimic the prevalent cerebral microvascular Aβ deposition observed in those patients, and the Swedish mutations (K670N/M671L) to increase Aβ production. In these Tg-SwDI mice, we have reported predominant fibrillar Aβ along microvessels in the thalamic region and diffuse plaques in cortical region. Concurrently, activated microglia and reactive astrocytes have been detected primarily in association with fibrillar cerebral microvascular Aβ in this model. Here we show that three native complement components in classical and alternative complement pathways, C1q, C3, and C4, are elevated in Tg-SwDI mice in regions rich in fibrillar microvascular Aβ. Immunohistochemical staining of all three proteins was increased in thalamus, hippocampus, and subiculum, but not frontal cortex. Western blot analysis showed significant increases of all three proteins in the thalamic region (with hippocampus) as well as the cortical region, except C3 that was below detection level in cortex. Also, in the thalamic region (with hippocampus), C1q and C3 mRNAs were significantly up-regulated. These complement proteins appeared to be expressed largely by activated microglial cells associated with the fibrillar microvascular Aβ deposits. Our findings demonstrate that Tg-SwDI mice exhibit elevated complement protein expression in response to fibrillar vascular Aβ deposition that is observed in patients with familial CAA.
PMCID: PMC2099424  PMID: 17877807
22.  Dissecting phenotypic traits linked to human resilience to Alzheimer’s pathology 
Brain  2013;136(8):2510-2526.
Clinico-pathological correlation studies and positron emission tomography amyloid imaging studies have shown that some individuals can tolerate substantial amounts of Alzheimer’s pathology in their brains without experiencing dementia. Few details are known about the neuropathological phenotype of these unique cases that might prove relevant to understanding human resilience to Alzheimer’s pathology. We conducted detailed quantitative histopathological and biochemical assessments on brains from non-demented individuals before death whose brains were free of substantial Alzheimer’s pathology, non-demented individuals before death but whose post-mortem examination demonstrated significant amounts of Alzheimer’s changes (‘mismatches’), and demented Alzheimer’s cases. Quantification of amyloid-β plaque burden, stereologically-based counts of neurofibrillary tangles, neurons and reactive glia, and morphological analyses of axons were performed in the multimodal association cortex lining the superior temporal sulcus. Levels of synaptic integrity markers, and soluble monomeric and multimeric amyloid-β and tau species were measured. Our results indicate that some individuals can accumulate equivalent loads of amyloid-β plaques and tangles to those found in demented Alzheimer’s cases without experiencing dementia. Analyses revealed four main phenotypic differences among these two groups: (i) mismatches had striking preservation of neuron numbers, synaptic markers and axonal geometry compared to demented cases; (ii) demented cases had significantly higher burdens of fibrillar thioflavin-S-positive plaques and of oligomeric amyloid-β deposits reactive to conformer-specific antibody NAB61 than mismatches; (iii) strong and selective accumulation of hyperphosphorylated soluble tau multimers into the synaptic compartment was noted in demented cases compared with controls but not in mismatches; and (iv) the robust glial activation accompanying amyloid-β and tau pathologies in demented cases was remarkably reduced in mismatches. Further biochemical measurements of soluble amyloid-β species—monomers, dimers and higher molecular weight oligomers—in total brain homogenates and synaptoneurosomal preparations failed to demonstrate significant differences between mismatches and demented cases. Together, these data suggest that amyloid-β plaques and tangles do not inevitably result in neural system derangement and dementia in all individuals. We identified distinct phenotypic characteristics in the profile of brain fibrillar and soluble amyloid-β and tau accrual and in the glial response that discriminated demented and non-demented individuals with high loads of Alzheimer’s pathology. Amyloid-β deposition in the form of fibrillar plaques and intimately related oligomeric amyloid-β assemblies, hyperphosphorylated soluble tau species localized in synapses, and glial activation emerged in this series as likely mediators of neurotoxicity and altered cognition, providing further insight into factors and pathways potentially involved in human susceptibility or resilience to Alzheimer’s pathological changes.
PMCID: PMC3722351  PMID: 23824488
Alzheimers disease; amyloid pathology; tau pathology; resilience; astrocytes; microglia
23.  A fibril-specific, conformation-dependent antibody recognizes a subset of Aβ plaques in Alzheimer disease, Down syndrome and Tg2576 transgenic mouse brain 
Acta Neuropathologica  2009;118(4):505-517.
Beta-amyloid (Aβ) is thought to be a key contributor to the pathogenesis of Alzheimer disease (AD) in the general population and in adults with Down syndrome (DS). Different assembly states of Aβ have been identified that may be neurotoxic. Aβ oligomers can assemble into soluble prefibrillar oligomers, soluble fibrillar oligomers and insoluble fibrils. Using a novel antibody, OC, recognizing fibrils and soluble fibrillar oligomers, we characterized fibrillar Aβ deposits in AD and DS cases. We further compared human specimens to those obtained from the Tg2576 mouse model of AD. Our results show that accumulation of fibrillar immunoreactivity is significantly increased in AD relative to nondemented aged subjects and those with select cognitive impairments (p < 0.0001). Further, there was a significant correlation between the extent of frontal cortex fibrillar deposit accumulation and dementia severity (MMSE r = −0.72). In DS, we observe an early age of onset and age-dependent accumulation of fibrillar OC immunoreactivity with little pathology in similarly aged non-DS individuals. Tg2576 mice show fibrillar accumulation that can be detected as young as 6 months. Interestingly, fibril-specific immunoreactivity was observed in diffuse, thioflavine S-negative Aβ deposits in addition to more mature neuritic plaques. These results suggest that fibrillar deposits are associated with disease in both AD and in adults with DS and their distribution within early Aβ pathology associated with diffuse plaques and correlation with MMSE suggest that these deposits may not be as benign as previously thought.
PMCID: PMC2737113  PMID: 19360426
Diffuse plaques; Frontal cortex; Transgenic mouse; Trisomy 21
24.  Blood pressure is associated with higher brain amyloid burden and lower glucose metabolism in healthy late middle-age persons 
Neurobiology of Aging  2011;33(4):827.e11-827.e19.
Epidemiological studies suggest that elevated blood pressure (BP) in mid-life is associated with increased risk of Alzheimer’s disease (AD) in late-life. In this preliminary study, we investigated the extent to which BP measurements are related to positron emission tomography (PET) measurements of fibrillar amyloid-beta burden using Pittsburgh Compound-B (PiB) and fluorodeoxyglucose (FDG) PET measures of cerebral metabolic rate for glucose metabolism (CMRgl) in cognitively normal, late-middle-aged to older adult apolipoprotein E (APOE) ε4 homozygotes, heterozygotes and non-carriers. PiB PET results revealed that systolic BP (SBP) and pulse pressure (PP) were each positively correlated with cerebral-to-cerebellar PiB distribution volume ratio (DVR) in frontal, temporal and posterior-cingulate/precuneus regions, whereas no significant positive correlations were found between PiB DVRs and diastolic BP (DBP). FDG PET results revealed significant inverse correlations between each of the BP measures and lower CMRgl in frontal and temporal brain regions. These preliminary findings provide additional evidence that higher BP, likely a reflection of arterial stiffness, during late-mid-life may be associated with increased risk of presymptomatic AD.
PMCID: PMC3236809  PMID: 21821316
APOE; blood pressure; arterial stiffness; brain imaging; PET; Alzheimer’s disease; amyloid; PiB; Pittsburgh Compound-B
25.  Early-Onset and Robust Amyloid Pathology in a New Homozygous Mouse Model of Alzheimer's Disease 
PLoS ONE  2009;4(11):e7931.
Transgenic mice expressing mutated amyloid precursor protein (APP) and presenilin (PS)-1 or -2 have been successfully used to model cerebral β-amyloidosis, one of the characteristic hallmarks of Alzheimer's disease (AD) pathology. However, the use of many transgenic lines is limited by premature death, low breeding efficiencies and late onset and high inter-animal variability of the pathology, creating a need for improved animal models. Here we describe the detailed characterization of a new homozygous double-transgenic mouse line that addresses most of these issues.
Methodology/Principal Findings
The transgenic mouse line (ARTE10) was generated by co-integration of two transgenes carrying the K670N/M671L mutated amyloid precursor protein (APPswe) and the M146V mutated presenilin 1 (PS1) both under control of a neuron-specific promoter. Mice, hemi- as well as homozygous for both transgenes, are viable and fertile with good breeding capabilities and a low rate of premature death. They develop robust AD-like cerebral β-amyloid plaque pathology with glial inflammation, signs of neuritic dystrophy and cerebral amyloid angiopathy. Using our novel image analysis algorithm for semi-automatic quantification of plaque burden, we demonstrate an early onset and progressive plaque deposition starting at 3 months of age in homozygous mice with low inter-animal variability and 100%-penetrance of the phenotype. The plaques are readily detected in vivo by PiB, the standard human PET tracer for AD. In addition, ARTE10 mice display early loss of synaptic markers and age-related cognitive deficits. By applying a γ-secretase inhibitor we show a dose dependent reduction of soluble amyloid β levels in the brain.
ARTE10 mice develop a cerebral β-amyloidosis closely resembling the β-amyloid-related aspects of human AD neuropathology. Unifying several advantages of previous transgenic models, this line particularly qualifies for the use in target validation and for evaluating potential diagnostic or therapeutic agents targeting the amyloid pathology of AD.
PMCID: PMC2775952  PMID: 19936202

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