Aβ Plaque Density Research Articles

FAM19A5 Deficiency Mitigates the Aβ Plaque Burden and Improves Cognition in Mouse Models of Alzheimer's Disease.

FAM19A5, a novel secretory protein highly expressed in the brain, is potentially associated with the progression of Alzheimer's disease (AD). However, its role in the AD pathogenesis remains unclear. Here, we investigated the potential function of FAM19A5 in the context of AD. We generated APP/PS1 mice with partial FAM19A5 deficiency, termed APP/PS1/FAM19A5+/LacZ mice. Compared with control APP/PS1 mice, APP/PS1/FAM19A5+/LacZ mice exhibited significantly lower Aβ plaque density and prolonged the lifespan of the APP/PS1 mice. To further explore the therapeutic potential of targeting FAM19A5, we developed a FAM19A5 antibody. Administration of this antibody to APP/PS1 mice significantly improved their performance in the Y-maze and passive avoidance tests, indicating enhanced cognitive function. This effect was replicated in 5XFAD mice, a model of early-onset AD characterized by rapid Aβ accumulation. Additionally, FAM19A5 antibody treatment in 5XFAD mice led to enhanced exploration of novel objects and increased spontaneous alternation behavior in the novel object recognition and Y-maze tests, respectively, indicating improved cognitive function. These findings suggest that FAM19A5 plays a significant role in AD pathology and that targeting with FAM19A5 antibodies may be a promising therapeutic strategy for AD.

Naringin Reduced the Density and Total Number of Aβ Plaques and Restored Memory Function and Volume of Hippocampal CA1 Area in Alzheimer's Disease Model Rats: A Stereological Study

Background: Alzheimer's disease (AD), the most prevalent form of dementia worldwide, is characterized by memory impairment and the accumulation of tau and beta-amyloid (Aβ) plaques. Naringin, a flavonoid, has exhibited strong anti-inflammatory, anti-oxidant, and anti-apoptotic properties. Objectives: In this study, we aimed to demonstrate the neuroprotective effects of naringin on memory function, the total number and density of Aβ plaques, and the volume of the hippocampal CA1 region in a scopolamine (SCO)-induced AD model in rats. Methods: Forty male Wistar rats were randomly divided into the following groups: A control group, a saline + SCO (3 mg/kg) group (pretreated with 200 µL saline), and 3 treatment groups receiving naringin at doses of 50 mg/kg/day + SCO, 100 mg/kg/day + SCO, and 200 mg/kg/day + SCO (pretreated with 50, 100, or 200 mg/kg of naringin) for 14 consecutive days via intraperitoneal (IP) injection. After the 14-day pretreatment period, the saline + SCO and 3 naringin treatment groups received SCO (3 mg/kg) to induce an AD-like condition. Memory function was assessed using the inhibitory passive avoidance test. Following brain harvesting, paraffin-embedded coronal brain slices were stained with Congo red, and the density and the total number of Aβ plaques and the volume of the hippocampal CA1 area were estimated using unbiased stereological techniques. Results: The results indicated that naringin significantly improved memory function, with the most pronounced effect observed in the naringin 200 mg/kg + SCO group. Stereological analysis revealed that SCO reduced the volume of the hippocampal CA1 area and increased the total number and density of Aβ plaques. Pretreatment with naringin significantly restored the hippocampal CA1 volume in the 200 mg/kg + SCO group compared to the saline + SCO group. Additionally, naringin reduced the total number and density of Aβ plaques, with the most significant decrease observed in the 200 mg/kg + SCO group. Conclusions: Naringin restored memory function and the volume of the hippocampal CA1 region while reducing the total number and density of Aβ plaques in a SCO-induced AD model in rats. This stereological study complements previous molecular research on naringin's neuroprotective effects in AD-like pathogenesis.

Effect of hormone replacement therapy on amyloid beta (Aβ) plaque density in the rhesus macaque amygdala.

Amyloid beta (Aβ) plaque density was examined in the amygdala of rhesus macaques, to elucidate the influence of age, diet and hormonal environment. Luminex technology was used to measure cerebrospinal fluid (CSF) concentrations of Aβ40 and Aβ42 across three decades, while immunohistochemistry was used to examine Aβ plaque density in the amygdala. Aβ40 was found to be the predominant isoform of Aβ in the CSF, but neither Aβ40 or Aβ42 concentrations showed an age-related change, and the ratio of Aβ42 to Aβ40 showed only a marginal increase. Significantly fewer Aβ plaques were detected in the amygdala of old ovariectomized animals if they received estradiol HRT (p < 0.001); similar results were obtained regardless of whether they had been maintained on a regular monkey chow for ∼48 months or on a high-fat, high-sugar, Western-style diet for ∼30 months. The results demonstrate that HRT involving estrogen can reduce Aβ plaque load in a cognitive brain region of aged non-human primates. The results from this translational animal model may therefore have clinical relevance to the treatment of AD in post-menopausal women, whether used alone, or as a supplement to current pharmacological and monoclonal antibody-based interventions.

Amyloid PET across the cognitive spectrum in former professional and college American football players: findings from the DIAGNOSE CTE Research Project

BackgroundExposure to repetitive head impacts (RHI) in American football players can lead to cognitive impairment and dementia due to neurodegenerative disease, particularly chronic traumatic encephalopathy (CTE). The pathognomonic lesion of CTE consists of perivascular aggregates of hyper-phosphorylated tau in neurons at the depths of cortical sulci. However, it is unclear whether exposure to RHI accelerates amyloid-β (Aβ) plaque formation and increases the risk for Alzheimer’s disease (AD). Although the Aβ neuritic plaques characteristic of AD are observed in a minority of later-stage CTE cases, diffuse plaques are more common. This study examined whether former professional and college American football players, including those with cognitive impairment and dementia, have elevated neuritic Aβ plaque density, as measured by florbetapir PET. Regardless of cognitive and functional status, elevated levels of florbetapir uptake were not expected.MethodsWe examined 237 men ages 45–74, including 119 former professional (PRO) and 60 former college (COL) football players, with and without cognitive impairment and dementia, and 58 same-age men without a history of contact sports or TBI (unexposed; UE) and who denied cognitive or behavioral symptoms at telephone screening. Former players were categorized into four diagnostic groups: normal cognition, subjective memory impairment, mild cognitive impairment, and dementia. Positive florbetapir PET was defined by cortical-cerebellar average SUVR of ≥ 1.10. Multivariable linear regression and analysis of covariance (ANCOVA) compared florbetapir average SUVR across diagnostic and exposure groups. Multivariable logistic regression compared florbetapir positivity. Race, education, age, and APOE4 were covariates.ResultsThere were no diagnostic group differences either in florbetapir average SUVR or the proportion of elevated florbetapir uptake. Average SUVR means also did not differ between exposure groups: PRO-COL (p = 0.94, 95% C.I. = [− 0.033, 0.025]), PRO-UE (p = 0.40, 95% C.I. = [− 0.010, 0.029]), COL-UE (p = 0.36, 95% CI = [0.0004, 0.039]). Florbetapir was not significantly associated with years of football exposure, cognition, or daily functioning.ConclusionsCognitive impairment in former American football players is not associated with PET imaging of neuritic Aβ plaque deposition. These findings are inconsistent with a neuropathological diagnosis of AD in individuals with substantial RHI exposure and have both clinical and medico-legal implications.Trial registrationNCT02798185.

Characterization of apathy-like behaviors and their relationship to Aβ pathology in 5xFAD mice.

Alzheimer's disease (AD) is a neurodegenerative disease that causes progressive cognitive decline and neuropsychiatric symptoms (NPS) with apathy being highly common. The neurobiological mechanisms of apathy in AD are unclear. This study characterized apathy-like behaviors in 5xFAD mice and their relationship to amyloid-beta (Aβ) pathology in the hippocampus and prefrontal cortex (PFC). We examined apathy-like behavior in male and female 5xFAD mice and wild-type controls at 6, 12, and 16 months of age (n=9-14 per group). Behavioral paradigms included nest building, marble burying, and food burrowing, and we calculated apathy composite scores for each mouse from the results of these three tests. Then, we measured soluble Aβ42 in the hippocampus and PFC of the male and female 5xFAD mice with the highest and lowest apathy composites within each age group by ELISA assay. Finally, we characterized Aβ plaque density and size in the hippocampal CA1 subregion and the PFC using thioflavin-S staining and ImageJ. Three-way, independent sample ANOVAs were conducted to determine the effects of age, gender, and genotype or apathy status on behavioral or biochemical outcomes, respectively. Apathy-like behaviors occurred in 5xFAD mice at all ages (p<.0001 at 6, 12, and 16 months), and these behaviors became more prominent with age. Females displayed more apathetic-like behaviors than males (p<.01). Soluble Aβ42 was substantially greater for 16-month than 6-month 5xFAD mice in the hippocampus (p<.0001) and PFC ( p<.001) and for 12-month than 6-month 5xFAD mice in the hippocampus (p<.01). Higher apathy composites were associated with greater soluble Aβ42 in the PFC and more plaques in the CA1 subregion than lower apathy composites (p<.05 for both). In the PFC, female 5xFAD mice had more plaques than males (p<.01). Plaque density in the CA1 subregion and plaque size in the PFC were greater in 12-month compared to 6-month 5xFAD mice (p<.05 for both). This study demonstrates that 5xFAD mice display apathy-like behaviors starting at 6 months that become significantly worse with age and potentially differ between sexes. Additionally, our study suggests correlations between apathy and soluble and insoluble Aβ pathology that differs by brain region.

Albiflorin alleviates cognitive dysfunction in STZ-induced rats.

Background: To explore the effect of albiflorin (AL) on streptozotocin (STZ)-induced Alzheimer's disease (AD) in rats.Methods: A mouse model of diabetic encephalopathy was established by intraperitoneal injection of 1%STZ. Step down test and water maze test were used to test the cognitive function of rats. Congo Red Staining was used to detect the distribution of Aβ plaques in the hippocampus of rats. Cytokine levels in serum and hippocampus were measured using ELISA. Serum insulin, oral glucose tolerance (OGTT), serum superoxide dismutase (SOD) activity and malondialdehyde (MDA) content were measured by commercial kits. And the content of Nrf-2/HO-1/HMGB1/NF-kB in the hippocampus of diabetic rats were detected by western blot.Results and Conclusion: Compared with the STZ model group, the average escape latency of rats in the AL group in the Morris water maze test was significantly shortened, and the average number of platform crossings and the ratio of distance/total swimming distance in the target quadrant were increased significantly. Staining of tissue sections and ELISA showed a decrease in Aβ plaque density in the hippocampus of rats in the AL group. And serum insulin levels of rats in the ALgroup were significantly reduced and OGTT was improved. In addition, AL could also regulate the Nrf-2/HO-1/HMGB1/NF-kB signal pathway in the hippocampus. Therefore, AL may ameliorate STZ-induced cognitive impairment in rats by regulating oxidative stress and inflammation in the brain.

Analysis of CX3CR1 haplodeficiency in male and female APPswe/PSEN1dE9 mice along Alzheimer disease progression

Microglia, the resident immune cells of the brain, have recently emerged as key players in Alzheimer Disease (AD) pathogenesis, but their roles in AD remain largely elusive and require further investigation. Microglia functions are readily altered when isolated from their brain environment, and microglia reporter mice thus represent valuable tools to study the contribution of these cells to neurodegenerative diseases such as AD. The CX3CR1+/eGFP mice is one of the most popular microglia reporter mice, and has been used in numerous studies to investigate in vivo microglial functions, including in the context of AD research. However, until now, the impact of CX3CR1 haplodeficiency on the typical features of Alzheimer Disease has not been studied in depth.To fill this gap, we generated APPswe/PSEN1dE9:CX3CR1+/eGFP mice and analyzed these mice for Alzheimer’s like pathology and neuroinflammation hallmarks. More specifically, using robust multifactorial statistical and multivariate analyses, we investigated the impact of CX3CR1 deficiency in both males and females, at three typical stages of the pathology progression: at early stage when Amyloid-β (Aβ) deposition just starts, at intermediate stage during Aβ accumulation phase and at more advanced stages when Aβ plaque number stabilizes. We found that CX3CR1 haplodeficiency had little impact on the progression of the pathology in the APPswe/PSEN1dE9 model and demonstrated that the APPswe/PSEN1dE9:CX3CR1+/eGFP line is a relevant and useful model to study the role of microglia in Alzheimer Disease. In addition, although Aβ plaques density is higher in females compared to age-matched males, we show that their glial reaction, inflammation status and memory deficits are not different.

Parvalbumin-Positive Neuron Loss and Amyloid-β Deposits in the Frontal Cortex of Alzheimer's Disease-Related Mice.

Alzheimer's disease (AD) has several hallmark features including amyloid-β (Aβ) plaque deposits and neuronal loss. Here, we characterized Aβ plaque aggregation and parvalbumin-positive (PV) GABAergic neurons in 6-9-month-old 5xFAD mice harboring mutations associated with familial AD. We used immunofluorescence staining to compare three regions in the frontal cortex-prelimbic (PrL), cingulate (Cg, including Cg1 and Cg2), and secondary motor (M2) cortices-along with primary somatosensory (S1) cortex. We quantified the density of Aβ plaques, which showed significant laminar and regional vulnerability. There were more plaques of larger sizes in deep layers compared to superficial layers. Total plaque burden was higher in frontal regions compared to S1. We also found layer- and region-specific differences across genotype in the density of PV interneurons. PV neuron density was lower in 5xFAD mice than wild-type, particularly in deep layers of frontal regions, with Cg (-50%) and M2 (-39%) exhibiting the largest reduction. Using in vivo two-photon imaging, we longitudinally visualized the loss of frontal cortical PV neurons across four weeks in the AD mouse model. Overall, these results provide information about Aβ deposits and PV neuron density in a widely used mouse model for AD, implicating deep layers of frontal cortical regions as being especially vulnerable.

Genetic deletion of CB1 cannabinoid receptors exacerbates the Alzheimer-like symptoms in a transgenic animal model

Activating CB1 cannabinoid receptor has been demonstrated to produce certain therapeutic effects in animal models of Alzheimer’s disease (AD). In this study, we evaluated the specific contribution of CB1 receptor to the progression of AD-like pathology in double transgenic APP/PS1 mice. A new mouse strain was generated by crossing APP/PS1 transgenic mice with CB1 knockout mice. Genetic deletion of CB1 drastically reduced the survival of APP/PS1 mice. In spite that CB1 mutant mice bearing the APP/PS1 transgene developed normally, they suddenly died within the first two months of life likely due to spontaneous seizures. This increased mortality could be related to an imbalance in the excitatory/inhibitory transmission in the hippocampus as suggested by the reduced density of inhibitory parvalbumin positive neurons observed in APP/PS1 mice lacking CB1 receptor at 7 weeks of age. We also evaluated the AD-like phenotype of APP/PS1 mice heterozygous for the CB1 deletion at 3 and 6 months of age. The memory impairment associated to APP/PS1 transgene was accelerated in these mice. Neither the soluble levels of Aβ or the density of Aβ plaques were modified in APP/PS1 mice heterozygous for CB1 deletion at any age. However, the reduction in CB1 receptor expression decreased the levels of PSD-95 protein in APP/PS1 mice, suggesting a synaptic dysfunction in these animals that could account for the acceleration of the memory impairment observed. In summary, our results suggest a crucial role for CB1 receptor in the progression of AD-related pathological events.

Brain amyloid burden and cerebrovascular disease are synergistically associated with neurometabolism in cognitively unimpaired older adults

Alzheimer's disease (AD) is the most common cause of cognitive dysfunction in older adults. The pathological hallmarks of AD such as beta amyloid (Aβ) aggregation and neurometabolic change, as indicated by altered myo-inositol (mI) and N-acetylaspartate (NAA) levels, typically precede the onset of cognitive dysfunction by years. Furthermore, cerebrovascular disease occurs early in AD, but the interplay between vascular and neurometabolic brain change is largely unknown. Thirty cognitively normal older adults (age = 70 ± 5.6 years, Mini-Mental State Examination = 29.2 ± 1) received 11-C-Pittsburgh Compound B positron emission tomography for estimating Aβ-plaque density, 7 Tesla fluid-attenuated inversion recovery magnetic resonance imaging for quantifying white matter hyperintensity volume as a marker of small vessel cerebrovascular disease and high-resolution magnetic resonance spectroscopic imaging at 7 Tesla, based on free induction decay acquisition localized by outer volume suppression to investigate tissue-specific neurometabolism in the posterior cingulate and precuneus. Aβ (β = 0.45, p = 0.018) and white matter hyperintensities (β = 0.40, p = 0.046) were independently and interactively (β = −0.49, p = 0.026) associated with a higher ratio of mI over NAA (mI/NAA) in the posterior cingulate and precuneus gray matter but not in the white matter. Our data suggest that cerebrovascular disease and Aβ burden are synergistically associated with AD-related gray matter neurometabolism in older adults.

Superparamagnetic nanoparticle-enhanced MRI of Alzheimer's disease plaques and activated microglia in 3X transgenic mouse brains: Contrast optimization.

To optimize magnetic resonance imaging (MRI) of antibody-conjugated superparamagnetic nanoparticles for detecting amyloid-β plaques and activated microglia in a 3X transgenic mouse model of Alzheimer's disease. Ten 3X Tg mice were fed either chow or chow containing 100 ppm resveratrol. Four brains, selected from animals injected with either anti-amyloid targeted superparamagnetic iron oxide nanoparticles, or anti-Iba-1-conjugated FePt-nanoparticles, were excised, fixed with formalin, and placed in Fomblin for ex vivo MRI (11.7T) using multislice-multiecho, multiple gradient echo, rapid acquisition with relaxation enhancement, and susceptibility-weighted imaging (SWI). Aβ plaques and areas of neuroinflammation appeared as hypointense regions whose number, location, and Z-score were measured as a function of sequence type and echo time. The MR contrast was due to the shortening of the transverse relaxation time of the plaque-adjacent tissue water. A theoretical analysis of this effect showed that the echo time was the primary determinant of plaque contrast and was used to optimize Z-scores. The Z-scores of the detected lesions varied from 21 to 34 as the echo times varied from 4 to 25 msec, with SWI providing the highest Z-score and number of detected lesions. Computation of the entire plaque and activated microglial distributions in 3D showed that resveratrol treatment led to a reduction of ∼24-fold of Aβ plaque density and ∼4-fold in microglial activation. Optimized MRI of antibody-conjugated superparamagnetic nanoparticles served to reveal the 3D distributions of both Aβ plaques and activated microglia and to measure the effects of drug treatments in this 3X Tg model. 1 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:574-588.

Amyloid pathology and axonal injury after brain trauma.

Objective:To image β-amyloid (Aβ) plaque burden in long-term survivors of traumatic brain injury (TBI), test whether traumatic axonal injury and Aβ are correlated, and compare the spatial distribution of Aβ to Alzheimer disease (AD).Methods:Patients 11 months to 17 years after moderate–severe TBI underwent 11C-Pittsburgh compound B (11C-PiB)-PET, structural and diffusion MRI, and neuropsychological examination. Healthy aged controls and patients with AD underwent PET and structural MRI. Binding potential (BPND) images of 11C-PiB, which index Aβ plaque density, were computed using an automatic reference region extraction procedure. Voxelwise and regional differences in BPND were assessed. In TBI, a measure of white matter integrity, fractional anisotropy, was estimated and correlated with 11C-PiB BPND.Results:Twenty-eight participants (9 with TBI, 9 controls, 10 with AD) were assessed. Increased 11C-PiB BPND was found in TBI vs controls in the posterior cingulate cortex and cerebellum. Binding in the posterior cingulate cortex increased with decreasing fractional anisotropy of associated white matter tracts and increased with time since injury. Compared to AD, binding after TBI was lower in neocortical regions but increased in the cerebellum.Conclusions:Increased Aβ burden was observed in TBI. The distribution overlaps with, but is distinct from, that of AD. This suggests a mechanistic link between TBI and the development of neuropathologic features of dementia, which may relate to axonal damage produced by the injury.

Dietary DHA supplementation in an APP/PS1 transgenic rat model of AD reduces behavioral and Aβ pathology and modulates Aβ oligomerization

Increased dietary consumption of docosahexaenoic acid (DHA) is associated with decreased risk for Alzheimer's disease (AD). These effects have been postulated to arise from DHA's pleiotropic effects on AD pathophysiology, including its effects on β-amyloid (Aβ) production, aggregation, and toxicity. While in vitro studies suggest that DHA may inhibit and reverse the formation of toxic Aβ oligomers, it remains uncertain whether these mechanisms operate in vivo at the physiological concentrations of DHA attainable through dietary supplementation. We sought to clarify the effects of dietary DHA supplementation on Aβ indices in a transgenic APP/PS1 rat model of AD. Animals maintained on a DHA-supplemented diet exhibited reductions in hippocampal Aβ plaque density and modest improvements on behavioral testing relative to those maintained on a DHA-depleted diet. However, DHA supplementation also increased overall soluble Aβ oligomer levels in the hippocampus. Further quantification of specific conformational populations of Aβ oligomers indicated that DHA supplementation increased fibrillar (i.e. putatively less toxic) Aβ oligomers and decreased prefibrillar (i.e. putatively more toxic) Aβ oligomers. These results provide in vivo evidence suggesting that DHA can modulate Aβ aggregation by stabilizing soluble fibrillar Aβ oligomers and thus reduce the formation of both Aβ plaques and prefibrillar Aβ oligomers. However, since fibrillar Aβ oligomers still retain inherent neurotoxicity, DHA may need to be combined with other interventions that can additionally reduce fibrillar Aβ oligomer levels for more effective prevention of AD in clinical settings.

Optical and SPION-enhanced MR imaging shows that trans-stilbene inhibitors of NF-κB concomitantly lower Alzheimer's disease plaque formation and microglial activation in AβPP/PS-1 transgenic mouse brain.

Alzheimer's disease (AD) is associated with a microglia-dependent neuroinflammatory response against plaques containing the fibrous protein amyloid-β (Aβ). Activation of microglia, which closely associate with Aβ plaques, engenders the release of pro-inflammatory cytokines and the internalization of Aβ fibrils. Since the pro-inflammatory transcription factor NF-κB is one of the major regulators of Aβ-induced inflammation, we treated transgenic amyloid-β protein protein/presenilin-1 (AβPP/PS1) mice for one year with a low dose (0.01% by weight in the diet) of either of two trans-stilbene NF-κB inhibitors, resveratrol or a synthetic analog LD55. The 3D distribution of Aβ plaques was measured ex vivo in intact brains at 60 μm resolution by quantitative magnetic resonance imaging (MRI) using blood-brain barrier-permeable, anti-AβPP-conjugated superparamagentic iron oxide nanoparticles (SPIONs). The MRI measurements were confirmed by optical microscopy of thioflavin-stained brain tissue sections and indicated that supplementation with either of the two trans-stilbenes lowered Aβ plaque density in the cortex, caudoputamen, and hippocampus by 1.4 to 2-fold. The optical measurements also included the hippocampus and indicated that resveratrol and LD55 reduced average Aβ plaque density by 2.3-fold and 3.1-fold, respectively. Ex vivo measurements of the regional distribution of microglial activation by Iba-1 immunofluorescence of brain tissue sections showed that resveratrol and LD55 reduced average microglial activation by 4.2- fold and 3.5-fold, respectively. Since LD55 lacked hydroxyl groups but both resveratrol and LD55 concomitantly reduced both Aβ plaque burden and neuroinflammation to a similar extent, it appears that the antioxidant potential of resveratrol is not an important factor in plaque reduction.

Alternative approaches for PET radiotracer development in Alzheimer's disease: imaging beyond plaque

Alzheimer's disease (AD) and related dementias show increasing clinical prevalence, yet our understanding of the etiology and pathobiology of disease-related neurodegeneration remains limited. In this regard, noninvasive imaging with radiotracers for positron emission tomography (PET) presents a unique tool for quantifying spatial and temporal changes in characteristic biological markers of brain disease and for assessing potential drug efficacy. PET radiotracers targeting different protein markers are being developed to address questions pertaining to the molecular and/or genetic heterogeneity of AD and related dementias. For example, radiotracers including [(11) C]-PiB and [(18) F]-AV-45 (Florbetapir) are being used to measure the density of Aβ-plaques in AD patients and to interrogate the biological mechanisms of disease initiation and progression. Our focus is on the development of novel PET imaging agents, targeting proteins beyond Aβ-plaques, which can be used to investigate the broader mechanism of AD pathogenesis. Here, we present the chemical basis of various radiotracers which show promise in preclinical or clinical studies for use in evaluating the phenotypic or biochemical characteristics of AD. Radiotracers for PET imaging neuroinflammation, metal ion association with Aβ-plaques, tau protein, cholinergic and cannabinoid receptors, and enzymes including glycogen-synthase kinase-3β and monoamine oxidase B amongst others, and their connection to AD are highlighted.

Comparison of the binding characteristics of [18F]THK-523 and other amyloid imaging tracers to Alzheimer’s disease pathology

Extensive deposition of senile plaques and neurofibrillary tangles in the brain is a pathological hallmark of Alzheimer's disease (AD). Although several PET imaging agents have been developed for in vivo detection of senile plaques, no PET probe is currently available for selective detection of neurofibrillary tangles in the living human brain. Recently, [(18)F]THK-523 was developed as a potential in vivo imaging probe for tau pathology. The purpose of this study was to compare the binding properties of [(18)F]THK-523 and other amyloid imaging agents, including PiB, BF-227 and FDDNP, to synthetic protein fibrils and human brain tissue. In vitro radioligand binding assays were conducted using synthetic amyloid β(42) and K18ΔK280-tau fibrils. Nonspecific binding was determined by the addition of unlabelled compounds at a concentration of 2μM. To examine radioligand binding to neuropathological lesions, in vitro autoradiography was conducted using sections of AD brain. [(18)F]THK-523 showed higher affinity for tau fibrils than for Aβ fibrils, whereas the other probes showed a higher affinity for Aβ fibrils. The autoradiographic analysis indicated that [(18)F]THK-523 accumulated in the regions containing a high density of tau protein deposits. Conversely, PiB and BF-227 accumulated in the regions containing a high density of Aβ plaques. These findings suggest that the unique binding profile of [(18)F]THK-523 can be used to identify tau deposits in AD brain.

Correlation of Amyloid PET Ligand Florbetapir F 18 Binding With Aβ Aggregation and Neuritic Plaque Deposition in Postmortem Brain Tissue

Florbetapir F 18 (F-AV-45) is a positron emission tomography imaging ligand for the detection of amyloid aggregation associated with Alzheimer disease. Earlier data showed that florbetapir F 18 binds with high affinity to β-amyloid (Aβ) plaques in human brain homogenates (Kd=3.7 nM) and has favorable imaging pharmacokinetic properties, including rapid brain penetration and washout. This study used human autopsy brain tissue to evaluate the correlation between in vitro florbetapir F 18 binding and Aβ density measured by established neuropathologic methods. The localization and density of florbetapir F 18 binding in frozen and formalin-fixed paraffin-embedded sections of postmortem brain tissue from 40 patients with a varying degree of neurodegenerative pathology was assessed by standard florbetapir F 18 autoradiography and correlated with the localization and density of Aβ identified by silver staining, thioflavin S staining, and immunohistochemistry. There were strong quantitative correlations between florbetapir F 18 tissue binding and both Aβ plaques identified by light microscopy (Silver staining and thioflavin S fluorescence) and by immunohistochemical measurements of Aβ using 3 antibodies recognizing different epitopes of the Aβ peptide. Florbetapir F 18 did not bind to neurofibrillary tangles. Florbetapir F 18 selectively binds Aβ in human brain tissue. The binding intensity was quantitatively correlated with the density of Aβ plaques identified by standard neuropathologic techniques and correlated with the density of Aβ measured by immunohistochemistry. As Aβ plaques are a defining neuropathologic feature for Alzheimer disease, these results support the use of florbetapir F 18 as an amyloid positron emission tomography ligand to identify the presence of Alzheimer disease pathology in patients with signs and symptoms of progressive late-life cognitive impairment.

Amyloid imaging

Molecular neuroimaging techniques such as PET are proving valuable in the early and differential diagnosis of Alzheimer's disease (AD).With the advent of new therapeutic strategies aimed at reducing β-amyloid (Aβ) burden in the brain to potentially prevent or delay functional and irreversible cognitive loss, there is increased interest in developing agents that allow assessment of Aβ burden in vivo. Amyloid imaging with PET has proven useful in the discrimination of dementias, showing significantly higher Aβ burden in the gray matter of AD patients when compared with healthy controls or patients with frontotemporal dementia. ApoE ε4 carriers, independent of diagnosis or disease severity, present with higher Aβ burden than non-ε4 carriers. Amyloid imaging matches histopathological reports in aging and dementia, reflecting the true regional density of Aβ plaques in cortical areas. It also appears to be more sensitive than FDG-PET for the diagnosis of AD. In healthy older people there is an increasing prevalence of amyloid positive scans with age, rising from 20% in the seventh decade to 60% in the ninth decade. Of people with mild cognitive impairment (MCI), 40-60% present with detectable cortical Aβ deposition. In both groups, Aβ deposition is associated with a higher risk for cognitive decline and dementia due to AD. These observations suggest that Aβ deposition is not part of normal aging, supporting the hypothesis that it occurs well before the onset of symptoms and is likely to represent preclinical AD in asymptomatic persons and prodromal AD in MCI. Further longitudinal observations, coupled with different disease-specific tracers and biomarkers, are required to confirm this hypothesis and further elucidate the precise role of Aβ deposition in the course of AD.

Amyloid Imaging in Alzheimer’s Disease and Other Dementias

With the advent of new therapeutic strategies aimed at reducing β-amyloid (Aβ) burden in the brain to potentially prevent or delay functional and irreversible cognitive loss, there is increased interest in developing agents that allow assessment of Aβ burden in vivo. Molecular neuroimaging techniques such as positron emission tomography (PET), in conjunction with related biomarkers in plasma and cerebrospinal fluid, are proving valuable in the early and differential diagnosis of Alzheimer's disease (AD). (11)C-PiB PET has proven useful in the discrimination of dementias, showing significantly higher PiB retention in grey matter of AD patients when compared with healthy controls or patients with frontotemporal dementia. (11)C-PiB PET also appears to be more accurate than FDG for the diagnosis of AD. Despite apparently underestimating the Aβ burden in the brain, (11)C-PiB PET is an optimal method to differentiate healthy controls from AD, matching histopathological reports in aging and dementia and reflecting the true regional density of Aβ plaques in cortical areas. High striatal Aβ deposition seems to be typical for carriers of familial forms of AD, whilst ApoE ε4 carriers, independent of diagnosis or disease severity, present with higher Aβ burden than non- ε4 carriers. Characterization of the binding properties of PiB has shown that despite binding to other misfolded proteins in vitro, PiB is extremely selective for Aβ at the concentrations achieved during a PET scan. Aβ burden as assessed by PET does not correlate with measures of cognition or cognitive decline in AD. Approximately 30% of apparently healthy older people, and 50-60% of people with mild cognitive impairment, present with cortical (11)C-PiB retention. In these groups, Aβ burden does correlate with episodic memory and rate of memory decline. These observations suggest that Aβ deposition is not part of normal ageing, supporting the hypothesis that Αβ deposition occurs well before the onset of symptoms and is likely to represent preclinical AD. Further longitudinal observations, coupled with different disease-specific tracers and biomarkers are required not only to confirm this hypothesis, but also to better elucidate the role of Αβ deposition in the course of Alzheimer's disease.

Amyloid Peptide Toxicity in an Animal Model of Alzheimer Disease

Amyloid Peptide Toxicity in an Animal Model of Alzheimer Disease