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The dopamine (DA) hypothesis postulates hyperactivity of subcortical DA transmission and hypoactivity of cortical DA in schizophrenia (SCH). Positron emission tomography provides the ability to assess this hypothesis in humans. However, no studies have examined the relationship between cortical DA and striatal DA in this illness.Dsub2/3/subreceptor radiotracer [sup11/supC]FLB457 BPsubND/sub(binding potential relative to nondisplaceable uptake) was measured in 14 off-medication subjects with SCH and 14 healthy control (HC) subjects at baseline and after the administration of 0.5 mg/kg oral d-amphetamine. The amphetamine-induced change in BPsubND/sub(ΔBPsubND/sub) was calculated as the difference between BPsubND/subin the postamphetamine condition and BPsubND/subin the baseline condition and expressed as a percentage of BPsubND/subat baseline. DA release in the striatum using the radiotracer [sup11/supC]NPA was also measured in these subjects.[sup11/supC]FLB457 ΔBPsubND/subwas greater in the HC group compared with the SCH group (Fsub1,26/sub = 5.7; p = .02) with significant differences in [sup11/supC]FLB457 ΔBPsubND/subseen across cortical brain regions. Only in the SCH group was a significant negative correlation observed between [sup11/supC]FLB457 ΔBPsubND/subin the dorsolateral prefrontal cortex and [sup11/supC]NPA ΔBPsubND/subin the dorsal caudate (r = -0.71, p = .005).Subjects with SCH demonstrated deficits of DA release in cortical brain regions relative to HC subjects. Examining both cortical and striatal DA release in the same subjects demonstrated an inverse relationship between cortical DA release and striatal DA release in SCH not present in HC subjects, providing support for the current DA hypothesis of SCH.

Early applications of positron emission tomography (PET) in psychiatry sought to identify derangements of cerebral blood flow and metabolism. The need for more specific neurochemical imaging probes was soon evident, and these probes initially targeted the sites of action of neuroleptic (dopamine D

Purpose: Previous studies from our lab utilized an ultra-high throughput screening method to identify compound 1 as a small molecule that binds to alpha-synuclein (α-synuclein) fibrils. The goal of the current study was to conduct a similarity search of 1 to identify structural analogs having improved in vitro binding properties for this target that could be labeled with radionuclides for both in vitro and in vivo studies for measuring α-synuclein aggregates. Methods: Using 1 as a lead compound in a similarity search, isoxazole derivative 15 was identified to bind to α-synuclein fibrils with high affinity in competition binding assays. A photocrosslinkable version was used to confirm binding site preference. Derivative 21, the iodo-analog of 15, was synthesized, and subsequently radiolabeled isotopologs [ 125I]21 and [ 11C]21 were successfully synthesized for use in in vitro and in vivo studies, respectively. [ 125I]21 was used in radioligand binding studies in post-mortem Parkinson’s disease (PD) and Alzheimer’s disease (AD) brain homogenates. In vivo imaging of an α-synuclein mouse model and non-human primates was performed with [ 11C]21. Results: In silico molecular docking and molecular dynamic simulation studies for a panel of compounds identified through a similarity search, were shown to correlate with K i values obtained from in vitro binding studies. Improved affinity of isoxazole derivative 15 for α-synuclein binding site 9 was indicated by photocrosslinking studies with CLX10. Design and successful (radio)synthesis of iodo-analog 21 of isoxazole derivative 15 enabled further in vitro and in vivo evaluation. K d values obtained in vitro with [ 125I]21 for α-synuclein and Aβ 42 fibrils were 0.48 ± 0.08 nM and 2.47 ± 1.30 nM, respectively. [ 125I]21 showed higher binding in human postmortem PD brain tissue compared with AD tissue, and low binding in control brain tissue. Lastly, in vivo preclinical PET imaging showed elevated retention of [ 11C]21 in PFF-injected mouse brain. However, in PBS-injected control mouse brain, slow washout of the tracer indicates high non-specific binding. [ 11C]21 showed high initial brain uptake in a healthy non-human primate, followed by fast washout that may be caused by rapid metabolic rate (21% intact [ 11C]21 in blood at 5 min p.i.). Conclusion: Through a relatively simple ligand-based similarity search, we identified a new radioligand that binds with high affinity (

With the emergence of positron emission tomography (PET) in the late 1970s, psychiatry had access to a tool capable of non-invasive assessment of human brain function. Early applications in psychiatry focused on identifying characteristic brain blood flow and metabolic derangements using radiotracers such as [

Individuals with familial Alzheimer’s disease due to PSEN1 mutations develop high cortical fibrillar amyloid-β load but often have lower cortical 11C-Pittsburgh compound B (PiB) retention than Individuals with sporadic Alzheimer’s disease. We hypothesized this is influenced by limited interactions of Pittsburgh compound B with cotton wool plaques, an amyloid-β plaque type common in familial Alzheimer’s disease but rare in sporadic Alzheimer’s disease. Histological sections of frontal and temporal cortex, caudate nucleus and cerebellum were obtained from 14 cases with sporadic Alzheimer’s disease, 12 cases with familial Alzheimer’s disease due to PSEN1 mutations, two relatives of a PSEN1 mutation carrier but without genotype information and three non-Alzheimer’s disease cases. Sections were processed immunohistochemically using amyloid-β-targeting antibodies and the fluorescent amyloid stains cyano-PiB and X-34. Plaque load was quantified by percentage area analysis. Frozen homogenates from the same brain regions from five sporadic Alzheimer’s disease and three familial Alzheimer’s disease cases were analysed for 3H-PiB in vitro binding and concentrations of amyloid-β1-40 and amyloid-β1-42. Nine sporadic Alzheimer’s disease, three familial Alzheimer’s disease and three non-Alzheimer’s disease participants had 11C-PiB PET with standardized uptake value ratios calculated using the cerebellum as the reference region. Cotton wool plaques were present in the neocortex of all familial Alzheimer’s disease cases and one sporadic Alzheimer’s disease case, in the caudate nucleus from four familial Alzheimer’s disease cases, but not in the cerebellum. Cotton wool plaques immunolabelled robustly with 4G8 and amyloid-β42 antibodies but weakly with amyloid-β40 and amyloid-βN3pE antibodies and had only background cyano-PiB fluorescence despite labelling with X-34. Relative to amyloid-β plaque load, cyano-Pittsburgh compound B plaque load was similar in sporadic Alzheimer’s disease while in familial Alzheimer’s disease it was lower in the neocortex and the caudate nucleus. In both regions, insoluble amyloid-β1-42 and amyloid-β1-40 concentrations were similar in familial Alzheimer’s disease and sporadic Alzheimer’s disease groups, while 3H-PiB binding was lower in the familial Alzheimer’s disease than the sporadic Alzheimer’s disease group. Higher amyloid-β1-42 concentration associated with higher 3H-PiB binding in sporadic Alzheimer’s disease but not familial Alzheimer’s disease. 11C-PiB retention correlated with region-matched post-mortem amyloid-β plaque load; however, familial Alzheimer’s disease cases with abundant cotton wool plaques had lower 11C-PiB retention than sporadic Alzheimer’s disease cases with similar amyloid-β plaque loads. PiB has limited ability to detect amyloid-β aggregates in cotton wool plaques and may underestimate total amyloid-β plaque burden in brain regions with abundant cotton wool plaques.

CBD-2115 was selected from a library of 148 compounds based on a pyridinyl-indole scaffold as a first-in-class 4R-tau radiotracer. In vitro binding assays showed [3H]CBD-2115 had a KD value of 6.9 nM and a nominal Bmax of 500 nM in 4R-tau expressing P301L transgenic mouse tissue. In binding assays with human brain tissue homogenates, [3H]CBD-2115 has a higher affinity (4.9 nM) for progressive supranuclear palsy specific 4R-tau deposits than [3H]flortaucipir (45 nM) or [3H]MK-6240 (>50 nM). [18F]CBD-2115 was reliably synthesized (3-11% radiochemical yield with molar activity of 27-111 GBq/μmol and >97% radiochemical purity). Dynamic PET imaging was conducted in mice, rats, and nonhuman primates, and all species showed initial brain uptake of 0.5-0.65 standardized uptake value with fast clearance from normal tissues. [3H]CBD-2115 could be a useful lead radioligand for further research in 4R-tauopathies, and PET radiotracer development will focus on improving brain uptake and binding affinity.

Introduction Positron emission tomography (PET) using radiolabeled amyloid-binding compounds has advanced the field of Alzheimer's disease (AD) by enabling detection and longitudinal tracking of fibrillar amyloid-β (Aβ) deposits in living people. However, this technique cannot distinguish between Aβ deposits in brain parenchyma (amyloid plaques) from those in blood vessels (cerebral amyloid angiopathy, CAA). Development of a PET radioligand capable of selectively detecting CAA would help clarify its contribution to global brain amyloidosis and clinical symptoms in AD and would help to characterize side-effects of anti-Aβ immunotherapies in AD patients, such as CAA. Methods A candidate CAA-selective compound (1) from a panel of analogues of the amyloid-binding dye Congo red was synthesized. The binding affinity to Aβ fibrils and lipophilicity of compound 1 were determined and selectivity for CAA versus parenchymal plaque deposits was assessed ex-vivo and in-vivo in transgenic APP/PS1 mice and in postmortem human brain affected with AD pathology. Results Compound 1 displays characteristics of Aβ binding dyes, such as thioflavin-S, in that it labels both parenchymal Aβ plaques and CAA when applied to histological sections from both a transgenic APP/PS1 mouse model of Aβ amyloidosis and AD brain. Thus, compound 1 lacks molecular selectivity to distinguish Aβ deposits in CAA from those in plaques. However, when administered to living APP/PS1 mice intravenously, compound 1 preferentially labels CAA when assessed using in-vivo two-photon microscopy and ex-vivo histology and autoradiography. Conclusion We hypothesize that selectivity of compound 1 for CAA is attributable to its limited penetration of the blood-brain barrier due to the highly polar nature of the carboxylate moiety, thereby limiting access to parenchymal plaques and promoting selective in-vivo labeling of Aβ deposits in the vascular wall (i.e., “delivery selectivity”).

In this review we examine, in the context of the amyloid, tau, and neurodegeneration framework, the available evidence and potential alternatives on how to establish tau positivity (T+) for multiple tau-imaging tracers in order to reach a consensus on normal and abnormal tau imaging values that can be universally implemented in clinical research and therapeutic trials.

Small Vessel Disease (SVD) is known to be associated with higher AD risk, but its relationship to amyloidosis in the progression of AD is unclear. In this cross-sectional study of cognitively normal older adults, we explored the interactive effects of SVD and amyloid-beta (Aβ) pathology on hippocampal functional connectivity during an associative encoding task and on hippocampal volume.This study included 61 cognitively normal older adults (age range: 65-93 years, age mean ± standard deviation: 75.8 ± 6.4, 41 [67.2%] female). PiB PET, T2-weighted FLAIR, T1-weighted and face-name fMRI images were acquired on each participant to evaluate brain Aβ, white matter hyperintensities (WMH+/- status), gray matter density, and hippocampal functional connectivity.We found that, in WMH (+) older adults greater Aβ burden was associated with greater hippocampal local connectivity (i.e., hippocampal-parahippocampal connectivity) and lower gray matter density in medial temporal lobe (MTL), whereas in WMH (-) older adults greater Aβ burden was associated with greater hippocampal distal connectivity (i.e., hippocampal-prefrontal connectivity) and no changes in MTL gray matter density. Moreover, greater hippocampal local connectivity was associated with MTL atrophy.These observations support a hippocampal excitotoxicity model linking SVD to neurodegeneration in preclinical AD. This may explain how SVD may accelerate the progression from Aβ positivity to neurodegeneration, and subsequent AD.

Important insights into the early pathogenesis of Alzheimer's disease can be provided by studies of autosomal dominant Alzheimer's disease and Down syndrome. However, it is unclear whether the timing and spatial distribution of amyloid accumulation differs between people with autosomal dominant Alzheimer's disease and those with Down syndrome. We aimed to directly compare amyloid changes between these two groups of people.In this cross-sectional study, we included participants (aged ≥25 years) with Down syndrome and sibling controls who had MRI and amyloid PET scans in the first data release (January, 2020) of the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study. We also included carriers of autosomal dominant Alzheimer's disease genetic mutations and non-carrier familial controls who were within a similar age range to ABC-DS participants (25-73 years) and had MRI and amyloid PET scans at the time of a data freeze (December, 2020) of the Dominantly Inherited Alzheimer Network (DIAN) study. Controls from the two studies were combined into a single group. All DIAN study participants had genetic testing to determine PSEN1, PSEN2, or APP mutation status. APOE genotype was determined from blood samples. CSF samples were collected in a subset of ABC-DS and DIAN participants and the ratio of amyloid β42 (Aβ42) to Aβ40 (Aβ42/40) was measured to evaluate its Spearman's correlation with amyloid PET. Global PET amyloid burden was compared with regards to cognitive status, APOE ɛ4 status, sex, age, and estimated years to symptom onset. We further analysed amyloid PET deposition by autosomal dominant mutation type. We also assessed regional patterns of amyloid accumulation by estimated number of years to symptom onset. Within a subset of participants the relationship between amyloid PET and CSF Aβ42/40 was evaluated.192 individuals with Down syndrome and 33 sibling controls from the ABC-DS study and 265 carriers of autosomal dominant Alzheimer's disease mutations and 169 non-carrier familial controls from the DIAN study were included in our analyses. PET amyloid centiloid and CSF Aβ42/40 were negatively correlated in carriers of autosomal dominant Alzheimer's disease mutations (n=216; r=-0·565; p0·0001) and in people with Down syndrome (n=32; r=-0·801; p0·0001). There was no difference in global PET amyloid burden between asymptomatic people with Down syndrome (mean 18·80 centiloids [SD 28·33]) versus asymptomatic mutation carriers (24·61 centiloids [30·27]; p=0·11) and between symptomatic people with Down syndrome (77·25 centiloids [41·76]) versus symptomatic mutation carriers (69·15 centiloids [51·10]; p=0·34). APOE ɛ4 status and sex had no effect on global amyloid PET deposition. Amyloid deposition was elevated significantly earlier in mutation carriers than in participants with Down syndrome (estimated years to symptom onset -23·0 vs -17·5; p=0·0002). PSEN1 mutations primarily drove this difference. Early amyloid accumulation occurred in striatal and cortical regions for both mutation carriers (n=265) and people with Down syndrome (n=128). Although mutation carriers had widespread amyloid accumulation in all cortical regions, the medial occipital regions were spared in people with Down syndrome.Despite minor differences, amyloid PET changes were similar between people with autosomal dominant Alzheimer's disease versus Down syndrome and strongly supported early amyloid dysregulation in individuals with Down syndrome. Individuals with Down syndrome aged at least 35 years might benefit from early intervention and warrant future inclusion in clinical trials, particularly given the relatively high incidence of Down syndrome.The National Institute on Aging, Riney and Brennan Funds, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the German Center for Neurodegenerative Diseases, and the Japan Agency for Medical Research and Development.

To characterize the influence of APOE genotype on cerebral Aβ load and longitudinal Aβ trajectories, [(11)C]PiB PET imaging studies were performed in a cohort of 428 participants with known APOE genotype and a range of clinical diagnoses from cognitively normal elderly to Alzheimer’s disease (AD). [(11)C]PiB PET imaging was used to assess amyloid load in a clinically heterogeneous cohort of 428 elderly participants. Serial [(11)C]PiB data and a repeated measures model were used to model amyloid trajectories in a subset of 235 participants classified on the basis of APOE genotype. We found that APOE-ε4 was associated with increased Aβ burden and an earlier age of onset of Aβ positivity, whereas APOE-ε2 appeared to have modest protective effects against Aβ. APOE class did not predict rates of Aβ accumulation. The present study suggests that APOE modifies AD risk through a direct influence on amyloidogenic processes, which manifests as an earlier age-of-onset of Aβ positivity, although it is likely that other genetic, environmental, and lifestyle factors are important.

Specificity and sensitivity of positron emission tomography (PET) radiopharmaceuticals targeting fibrillar amyloid-β (Aβ) deposits is high for detection of neuritic Aβ plaques, a mature form of Aβ deposits which often have dense Aβ core (i.e., cored plaques). However, imaging-to-autopsy validation studies of amyloid PET radioligands have identified several false positive cases all of which had mainly diffuse Aβ plaques (i.e., plaques without neuritic pathology or dense amyloid core), and high amyloid PET signal was reported in the striatum where diffuse plaques predominate in Alzheimer’s disease (AD). Relative contributions of different plaque types to amyloid PET signal is unclear, particularly in neocortical areas where they are intermixed in AD. In vitro binding assay and autoradiography were performed using [3H]flutemetamol and [3H]Pittsburgh Compound-B (PiB) in frozen brain homogenates from 30 autopsy cases including sporadic AD and non-AD controls with a range of brain Aβ burden and plaque density. Fixed tissue sections of frontal cortex and caudate from 10 of the AD cases were processed for microscopy using fluorescent derivatives of flutemetamol (cyano-flutemetamol) and PiB (cyano-PiB) and compared to Aβ immunohistochemistry and pan-amyloid (X-34) histology. Using epifluorescence microscopy, percent area coverage and fluorescence output values of cyano-PiB- and cyano-flutemetamol-labeled plaques in two-dimensional microscopic fields were then calculated and combined to obtain integrated density measurements. Using confocal microscopy, we analysed total fluorescence output of the entire three-dimensional volume of individual cored plaques and diffuse plaques labeled with cyano-flutemetamol or cyano-PiB. [3H]Flutemetamol and [3H]PiB binding values in tissue homogenates correlated strongly and their binding pattern in tissue sections, as seen on autoradiograms, overlapped the pattern of Aβ-immunoreactive plaques on directly adjacent sections. Cyano-flutemetamol and cyano-PiB fluorescence was prominent in cored plaques and less so in diffuse plaques. Across brain regions and cases, percent area coverage of cyano-flutemetamol-labeled plaques correlated strongly with cyano-PiB-labeled and Aβ-immunoreactive plaques. For both ligands, plaque burden, calculated as percent area coverage of all Aβ plaque types, was similar in frontal cortex and caudate regions, while integrated density values were significantly greater in frontal cortex, which contained both cored plaques and diffuse plaques, compared to the caudate, which contained only diffuse plaques. Three-dimensional analysis of individual plaques labeled with either ligand showed that total fluorescence output of a single cored plaque was equivalent to total fluorescence output of approximately three diffuse plaques of similar volume. Our results indicate that [18F]flutemetamol and [11C]PiB PET signal is influenced by both diffuse plaques and cored plaques, and therefore is likely a function of plaque size and density of Aβ fibrils in plaques. Brain areas with large volumes/frequencies of diffuse plaques could yield [18F]flutemetamol and [11C]PiB PET retention levels comparable to brain regions with a lower volume/frequency of cored plaques.

Tau PET tracers exhibit varying levels of specific signal and distinct off-target binding patterns that are more diverse than amyloid PET tracers. This study compared 2 frequently used tau PET tracers, (18)F-flortaucipir and (18)F-MK-6240, in the same subjects. Methods: (18)F-flortaucipir and (18)F-MK-6240 scans were collected within 2 mo in 15 elderly subjects varying in clinical diagnosis and cognition. FreeSurfer, version 5.3, was applied to 3-T MR images to segment Braak pathologic regions (I–VI) for PET analyses. Off-target binding was assessed in the choroid plexus, meninges, and striatum. SUV ratio (SUVR) outcomes were determined over 80–100 min ((18)F-flortaucipir) or 70–90 min ((18)F-MK-6240) normalized to cerebellar gray matter. Masked visual interpretation of images was performed by 5 raters for both the medial temporal lobe and the neocortex, and an overall (majority) rating was determined. Results: Overall visual ratings showed complete concordance between radiotracers for both the medial temporal lobe and the neocortex. SUVR outcomes were highly correlated (r(2) > 0.92; P ≪ 0.001) for all Braak regions except Braak II. The dynamic range of SUVRs in target regions was approximately 2-fold higher for (18)F-MK-6240 than for (18)F-flortaucipir. Cerebellar SUVs were similar for (18)F-MK-6240 and (18)F-flortaucipir, suggesting that differences in SUVRs are driven by specific signals. Apparent off-target binding was observed often in the striatum and choroid plexus with (18)F-flortaucipir and most often in the meninges with (18)F-MK-6240. Conclusion: Both (18)F-MK-6240 and (18)F-flortaucipir are capable of quantifying signal in a common set of brain regions that develop tau pathology in Alzheimer disease; these tracers perform equally well in visual interpretations. Each also shows distinct patterns of apparent off-target binding. (18)F-MK-6240 showed a greater dynamic range in SUVR estimates, which may be an advantage in detecting early tau pathology or in performing longitudinal studies to detect small interval changes.

The Alzheimer’s Disease Neuroimaging Initiative showed that Japanese had significantly lower brain Aβ burden than Americans among a cognitively normal population. This cross-sectional study aimed to compare vascular disease burden, Aβ burden, and neurodegeneration between cognitively normal elderly Japanese and Americans. Japanese and American participants were matched for age (±4-year-old), sex, and Apolipoprotein E (APOE) genotype. Brain vascular disease burden and brain Aβ burden were measured using white matter lesions (WMLs) and 11C-labeled Pittsburgh Compound B (PiB) retention, respectively. Neurodegeneration was measured using hippocampal volumes and cortical thickness. A total of 95 Japanese and 95 Americans were recruited (50.5% men, mean age = 82). Compared to Americans, Japanese participants had larger WMLs, and a similar global Aβ standardized uptake value ratio (SUVR), cortical thickness and hippocampal volumes. Japanese had significantly lower regional Aβ SUVR in the anterior ventral striatum, posterior cingulate cortex, and precuneus. Cognitively normal elderly Japanese and Americans had different profiles regarding vascular disease and Aβ burden. This suggests that multiple risk factors are likely to be involved in the development of dementia. Additionally, Japanese might have a lower risk of dementia due to lower Aβ burden than Americans. Longitudinal follow-up of these cohorts is warranted to ascertain the predictive accuracy of these findings.

We hypothesized that lower untreated systolic blood pressure (SBP) would be associated with a lower risk of dementia and death up to age 95.SBP measured between 2000 and 2006 was evaluated in relationship to dementia risk and brain biomarkers from 2009-2020 (n = 177) in the Gingko Evaluation of Memory Study (GEMS), mean age 95 in 2020. Participants had measurements of brain amyloid beta (Aβ) and repeat clinical-cognitive evaluations every 6 months.By 2020, only 9 of 177 patients (5%) were alive and cognitively unimpaired (CU). Mean SBP from 2000 to 2006 was 120 mm Hg for nine alive/CU, 125 mm Hg for alive/mild cognitive impairment (MCI), and 130 mm Hg for alive/dementia (P = .03). The amount of Aβ was directly related to SBP levels. In multivariate analysis, Aβ+ in 2009 and thinner cortex were significant predictors of dementia. Excluding Aβ, SBP became a significant predictor of dementia.Low SBP untreated by antihypertensive medications was associated with significant decreased risk of dementia and less Aβ.

Compared to men, women are disproportionally affected by Alzheimer's disease (AD) and have an accelerated trajectory of cognitive decline and disease progression. Neurobiological factors underlying gender differences in AD remain unclear. This study investigated brain beta-amyloid (Aβ)-related neural system differences in cognitively normal older men and women (N = 61; 41 females, 65–93 years old). We found that men and women showed different associations between Aβ load and hippocampal functional connectivity. During associative memory encoding, in men greater Aβ burden was accompanied by greater hippocampus-prefrontal connectivity (i.e., more synchronized activities), whereas in women hippocampal connectivity did not vary by Aβ burden. For resting-state data, the interaction of gender × Aβ on hippocampal connectivity did not survive multiple comparison in the whole-brain analyses. In the region of interest–based analyses, resting-state hippocampal-prefrontal connectivity was positively correlated with Aβ load in men and was negatively correlated with Aβ load in women. The observed Aβ-related neural differences may explain the accelerated trajectory of cognitive decline and AD progression in women.

Background:Observational studies in Asia show that dietary intake of soy isoflavones had a significant inverse association with coronary heart disease (CHD). A recent randomized controlled trial (RCT) of soy isoflavones on atherosclerosis in the US, however, failed to show their benefit. The discrepancy may be due to the much lower prevalence of S-equol producers in Westerners: Only 20-30% of Westerners produce S-equol in contrast to 50-70% in Asians. S-equol is a metabolite of dietary soy isoflavone daidzein by gut microbiome and possesses the most antiatherogenic properties among all isoflavones. Several short-duration RCTs documented that soy isoflavones improves arterial stiffness. Accumulating evidence shows that both atherosclerosis and arterial stiffness are positively associated with cognitive decline/dementia. Therefore, potentially, soy isoflavones, especially S-equol, are protective against cognitive decline/dementia. Methods/Results: This narrative review of clinical and epidemiological studies provides an overview of the health benefits of soy isoflavones and introduces S-equol. Second, we review recent evidence on the association of soy isoflavones and S-equol with CHD, atherosclerosis, and arterial stiffness as well as the association of atherosclerosis and arterial stiffness with cognitive decline/ dementia. Third, we highlight recent studies that report the association of soy isoflavones and S-equol with cognitive decline/dementia. Lastly, we discuss the future directions of clinical and epidemiological research on the relationship of S-equol and CHD and dementia.Conclusions:Evidence from observational studies and short-term RCTs suggests that S-equol is anti-atherogenic and improves arterial stiffness and may prevent CHD and cognitive impairment/ dementia. Well-designed long-term (≥ 2years) RCTs should be pursued.

Down syndrome (DS) predisposes individuals to early Alzheimer's disease (AD). Using Pittsburgh Compound B ([11C]PiB), a pattern of striatal amyloid beta (Aβ) that is elevated relative to neocortical binding has been reported, similar to that of nondemented autosomal dominant AD mutation carriers. However, it is not known whether changes in striatal and neocortical [11C]PiB retention differ over time in a nondemented DS population when compared to changes in a nondemented elderly (NDE) population. The purpose of this work was to assess longitudinal changes in trajectories of Aβ in a nondemented DS compared to an NDE cohort. The regional trajectories for anterior ventral striatum (AVS), frontal cortex, and precuneus [11C]PiB retention were explored over time using linear mixed effects models with fixed effects of time, cohort, and time-by-cohort interactions and subject as random effects. Significant differences between DS and NDE cohort trajectories for all 3 region of interests were observed (p < 0.05), with the DS cohort showing a faster accumulation in the AVS and slower accumulation in the frontal cortex and precuneus compared to the NDE cohort. These data add to the previously reported distinct pattern of early striatal deposition not commonly seen in sporadic AD by demonstrating that individuals with DS may also accumulate Aβ at a rate faster in the AVS when compared to NDE subjects.

Background: Subjective cognitive decline (SCD) may be an early manifestation of pre-clinical Alzheimer’s disease. Elevated amyloid-β (Aβ) is a correlate of SCD symptoms in some individuals. The underlying neural correlates of SCD symptoms and their association with Aβ is unknown. SCD is a heterogeneous condition, and cognitive reserve may explain individual differences in its neural correlates. Objective: We investigated the association between brain activation during memory encoding and SCD symptoms, as well as with Aβ, among older individuals. We also tested the moderating role of education (an index of cognitive reserve) on the associations. Methods: We measured brain activation during the “face-name” memory-encoding fMRI task and Aβ deposition with Pittsburgh Compound-B (PiB)-PET among cognitively normal older individuals (n = 63, mean age 73.1 ± 7.4 years). We tested associations between activation and SCD symptoms by self-report measures, Aβ, and interactions with education. Results: Activation was not directly associated with SCD symptoms or Aβ. However, education moderated the association between activation and SCD symptoms in the executive control network, salience network, and subcortical regions. Greater SCD symptoms were associated with greater activation in those with higher education, but with lower activation in those with lower education. Conclusion: SCD symptoms were associated with different patterns of brain activation in the extended memory system depending on level of cognitive reserve. Greater SCD symptoms may represent a saturation of neural compensation in individuals with greater cognitive reserve, while it may reflect diminishing neural resources in individuals with lower cognitive reserve.

Introduction Adults with Down syndrome (DS) are predisposed to Alzheimer's disease (AD) and reveal early amyloid beta (Aβ) pathology in the brain. Positron emission tomography (PET) provides an in vivo measure of Aβ throughout the AD continuum. Due to the high prevalence of AD in DS, there is need for longitudinal imaging studies of Aβ to better characterize the natural history of Aβ accumulation, which will aid in the staging of this population for clinical trials aimed at AD treatment and prevention. Methods Adults with DS (N = 79; Mean age (SD) = 42.7 (7.28) years) underwent longitudinal [C-11]Pittsburgh compound B (PiB) PET. Global Aβ burden was quantified using the amyloid load metric (AβL). Modeled PiB images were generated from the longitudinal AβL data to visualize which regions are most susceptible to Aβ accumulation in DS. AβL change was evaluated across Aβ(-), Aβ-converter, and Aβ(+) groups to assess longitudinal Aβ trajectories during different stages of AD-pathology progression. AβL change values were used to identify Aβ-accumulators within the Aβ(-) group prior to reaching the Aβ(+) threshold (previously reported as 20 AβL) which would have resulted in an Aβ-converter classification. With knowledge of trajectories of Aβ(-) accumulators, a new cutoff of Aβ(+) was derived to better identify subthreshold Aβ accumulation in DS. Estimated sample sizes necessary to detect a 25% reduction in annual Aβ change with 80% power (alpha 0.01) were determined for different groups of Aβ-status. Results Modeled PiB images revealed the striatum, parietal cortex and precuneus as the regions with earliest detected Aβ accumulation in DS. The Aβ(-) group had a mean AβL change of 0.38 (0.58) AβL/year, while the Aβ-converter and Aβ(+) groups had change of 2.26 (0.66) and 3.16 (1.34) AβL/year, respectively. Within the Aβ(-) group, Aβ-accumulators showed no significant difference in AβL change values when compared to Aβ-converter and Aβ(+) groups. An Aβ(+) cutoff for subthreshold Aβ accumulation was derived as 13.3 AβL. The estimated sample size necessary to detect a 25% reduction in Aβ was 79 for Aβ(-) accumulators and 59 for the Aβ-converter/Aβ(+) group in DS. Conclusion Longitudinal AβL changes were capable of distinguishing Aβ accumulators from non-accumulators in DS. Longitudinal imaging allowed for identification of subthreshold Aβ accumulation in DS during the earliest stages of AD-pathology progression. Detection of active Aβ deposition evidenced by subthreshold accumulation with longitudinal imaging can identify DS individuals at risk for AD development at an earlier stage.

CBD-2115 was selected from a library of 148 compounds based on a pyridinyl-indole scaffold as a first-in-class 4R-tau radiotracer. In vitro binding assays showed [(3)H]CBD-2115 had a K(D) value of 6.9 nM and a nominal B(max) of 500 nM in 4R-tau expressing P301L transgenic mouse tissue. In binding assays with human brain tissue homogenates, [(3)H]CBD-2115 has a higher affinity (4.9 nM) for progressive supranuclear palsy specific 4R-tau deposits than [(3)H]Flortaucipir (45 nM) or [(3)H]MK-6240 (>50 nM). [(18)F]CBD-2115 was reliably synthesized (3–11% radiochemical yield with molar activity of 27 – 111 GBq/μmol and >97% radiochemical purity). Dynamic PET imaging was conducted in mice, rats and non-human primate and all species showed initial brain uptake of 0.5–0.65 standardized uptake value with fast clearance from normal tissues. [(3)H]CBD-2115 could be a useful lead radioligand for further research in 4R-tauopathies, and PET radiotracer development will focus on improving brain uptake and binding affinity.

Highlights • Neurofibrillary tau deposition in Down syndrome follows the Braak staging pathology. • Neurofibrillary tau emerges in individuals with very low amyloid burden. • There is a short latency between the onset of amyloid and tau in Down syndrome. • Elevated tau was observed in Braak stages I-II with very low amyloid burden, and in stages III-VI with greater amyloid burden., Introduction Adults with Down syndrome are genetically predisposed to develop Alzheimer’s disease and accumulate beta-amyloid plaques (Aβ) early in life. While Aβ has been heavily studied in Down syndrome, its relationship with neurofibrillary tau is less understood. The aim of this study was to evaluate neurofibrillary tau deposition in individuals with Down syndrome with varying levels of Aβ burden. Methods A total of 161 adults with Down syndrome (mean age = 39.2 (8.50) years) and 40 healthy, non-Down syndrome sibling controls (43.2 (12.6) years) underwent T1w-MRI, [C-11]PiB and [F-18]AV-1451 PET scans. PET images were converted to units of standardized uptake value ratios (SUVrs). Aβ burden was calculated using the amyloid load metric (AβL); a measure of global Aβ burden that improves quantification from SUVrs by suppressing the nonspecific binding signal component and computing the specific Aβ signal from all Aβ-carrying voxels from the image. Regional tau was assessed using control-standardized AV-1451 SUVr. Control-standardized SUVrs were compared across Down syndrome groups of Aβ-negative (A-) (AβL

Introduction Equol, a metabolite of a soy isoflavone transformed by the gut microbiome, is anti‐oxidant and anti‐amyloidogenic. We assessed the associations of equol with white matter lesion normalized to total brain volume (WML%) and amyloid beta (Aβ) deposition. Methods From 2016 to 2018, 91 cognitively normal elderly Japanese aged 75 to 89 underwent brain magnetic resonance imaging and positron emission tomography using 11C‐Pittsburgh compound‐B. Serum equol was measured using stored samples from 2008 to 2012. Equol producers were defined as individuals with serum levels >0. Producers were further divided into high (> the median) and low (≤ the median) producers. Results The median (interquartile range) WML% was 1.10 (0.59 to 1.61); 24.2% were Aβ positive, and 51% were equol producers. Equol‐producing status (non‐producers, low and high) was significantly inversely associated with WML%: 1.19, 0.89, and 0.58, respectively (trend P

Harmonization of magnetic resonance imaging (MRI) and positron emission tomography (PET) scans from multi-scanner and multi-site studies presents a challenging problem. We applied the Removal of Artificial Voxel Effect by Linear regression (RAVEL) method to normalize T1-MRI intensities collected on two different scanners across two different sites as part of the Neurodegeneration in Aging Down syndrome (NiAD) study. The effects on FreeSurfer regional cortical thickness and volume outcome measures, in addition to FreeSurfer-based regional quantification of amyloid PET standardized uptake value ratio (SUVR) outcomes, were evaluated. A neuroradiologist visually assessed the accuracy of FreeSurfer hippocampus segmentations with and without the application of RAVEL. Quantitative results demonstrated that the application of RAVEL intensity normalization prior to running FreeSurfer significantly impacted both FreeSurfer volume and cortical thickness outcome measures. Visual assessment demonstrated that the application of RAVEL significantly improved FreeSurfer hippocampal segmentation accuracy. The RAVEL intensity normalization had little impact on PET SUVR measures.

Deposition of amyloid plaques in the brain is one of the two main pathological hallmarks of Alzheimer’s disease (AD). Amyloid positron emission tomography (PET) is a neuroimaging tool that selectively detects in vivo amyloid deposition in the brain and is a reliable endophenotype for AD that complements cerebrospinal fluid biomarkers with regional information. We measured in vivo amyloid deposition in the brains of ~1000 subjects from three collaborative AD centers and ADNI using 11C-labeled Pittsburgh Compound-B (PiB)-PET imaging followed by meta-analysis of genome-wide association studies, first to our knowledge for PiB-PET, to identify novel genetic loci for this endophenotype. The APOE region showed the most significant association where several SNPs surpassed the genome-wide significant threshold, with APOE*4 being most significant (P-meta = 9.09E-30; β = 0.18). Interestingly, after conditioning on APOE*4, 14 SNPs remained significant at P APOE region that were not in linkage disequilibrium with APOE*4. Outside the APOE region, the meta-analysis revealed 15 non-APOE loci with P P-meta = 4.87E-07) and 3 (P-meta = 9.69E-07). Functional analyses of these SNPs indicate their potential relevance with AD pathogenesis. Top 15 non-APOE SNPs along with APOE*4 explained 25–35% of the amyloid variance in different datasets, of which 14–17% was explained by APOE*4 alone. In conclusion, we have identified novel signals in APOE and non-APOE regions that affect amyloid deposition in the brain. Our data also highlights the presence of yet to be discovered variants that may be responsible for the unexplained genetic variance of amyloid deposition.

Introduction We sought to establish the relationships between standard postmortem measures of AD neuropathology and antemortem [ 11 C]PIB–positron emission tomography ([ 11 C]PIB-PET) analyzed with the Centiloid (CL) method, a standardized scale for Aβ-PET quantification. Methods Four centers contributed 179 participants encompassing a broad range of clinical diagnoses, PET data, and autopsy findings. Results CL values increased with each CERAD neuritic plaque score increment (median −3 CL for no plaques and 92 CL for frequent plaques) and nonlinearly with Thal Aβ phases (increases were detected starting at phase 2) with overlap between scores/phases. PET-pathology associations were comparable across sites and unchanged when restricting the analyses to the 56 patients who died within 2 years of PET. A threshold of 12.2 CL detected CERAD moderate-to-frequent neuritic plaques (area under the curve = 0.910, sensitivity = 89.2%, specificity = 86.4%), whereas 24.4 CL identified intermediate-to-high AD neuropathological changes (area under the curve = 0.894, sensitivity = 84.1%, specificity = 87.9%). Discussion Our study demonstrated the robustness of a multisite Centiloid [ 11 C]PIB-PET study and established a range of pathology-based CL thresholds.

Objective: To determine serotonin system abnormalities related to major depression or previous suicidal behavior.Methods: [11C]WAY100635, [18F]altanserin and positron emission tomography were used ...

The positron emission tomography (PET) radiotracer Pittsburgh Compound B ([C-11]PiB) demonstrates a high affinity for fibrillary amyloid-beta (Aβ) aggregates. However, [C-11]PiB's in vivo sensitivity and specificity is an ongoing area of investigation in correlation studies with postmortem measures of Aβ pathology. One potential confound in PET-to-postmortem correlation studies is the limited spatial resolution of PET and resulting partial volume effects (PVEs). In this work, we evaluated the impact of three partial volume correction (PVC) techniques – the Meltzer, the modified Müller-Gärtner, and the Region-Based Voxel-Wise – on correlations between region-matched in vivo [C-11]PiB standardized uptake value ratios (SUVRs) and postmortem measures of Aβ pathology in a unique cohort of nine subjects. Postmortem Aβ pathology was assessed histologically as percent area coverage of 6-CN-PiB positive and Aβ immunoreactive (4G8 antibody) deposits. The application of all three PVC techniques resulted in minimally reduced PET-to-postmortem correlations relative to no PVC. However, correlations to both 6-CN-PiB and 4G8 percent area across all PVC techniques and no PVC were statistically significant at p, Highlights • Three partial volume correction techniques are applied to PiB PET SUVR data. • Corrected and uncorrected data are correlated to postmortem measures of Aβ load. • All 3 correction methods minimally impact PET-to-postmortem correlations.

Background The Down syndrome (DS) population is genetically predisposed to amyloid-β protein precursor overproduction and Alzheimer's disease (AD). Objective The temporal ordering and spatial association between amyloid-β, glucose metabolism, and gray matter (GM) volume in the DS population can provide insight into those associations in the more common sporadic AD. Methods Twenty-four adults (13 male, 11 female; 39±7 years) with DS underwent [11C]PiB, [18F]FDG, and volumetric MRI scans. Voxel-wise associations between PiB SUVR, FDG SUVR, and GM volume were investigated, with and without individual adjustments for variables of interest. Results Positive associations of PiB and age were widespread throughout the neocortex and striatum. Negative associations of FDG and age (frontal, parietal, and temporal cortex) and of GM volume and age (frontal and insular cortex) were observed. PiB and FDG were negatively associated in parietal cortex, after adjustment for GM volume. Conclusions In adults with DS, early amyloid-β accumulation in the striatum is divergent from sporadic AD; however, despite the early striatal amyloid-β, glucose hypometabolism was confined to the typical AD-associated regions, which occurs similarly in autosomal dominant AD. Importantly, the glucose hypometabolism was not explained solely by increased partial volume effect due to GM volume reductions.

Objective Recent studies have shown that positron emission tomography (PET) tracer AV-1451 exhibits high binding affinity for paired helical filament (PHF)-tau pathology in Alzheimer's brains. However, the ability of this ligand to bind to tau lesions in other tauopathies remains controversial. Our goal was to examine the correlation of in vivo and postmortem AV-1451 binding patterns in three autopsy-confirmed non-Alzheimer tauopathy cases. Methods We quantified in vivo retention of [F-18]-AV-1451 and performed autoradiography, [H-3]-AV-1451 binding assays, and quantitative tau measurements in postmortem brain samples from two progressive supranuclear palsy (PSP) cases and a MAPT P301L mutation carrier. They all underwent [F-18]-AV-1451 PET imaging before death. Results The three subjects exhibited [F-18]-AV-1451 in vivo retention predominantly in basal ganglia and midbrain. Neuropathological examination confirmed the PSP diagnosis in the first two subjects; the MAPT P301L mutation carrier had an atypical tauopathy characterized by grain-like tau-containing neurites in gray and white matter with heaviest burden in basal ganglia. In all three cases, autoradiography failed to show detectable [F-18]-AV-1451 binding in multiple brain regions examined, with the exception of entorhinal cortex (reflecting incidental age-related neurofibrillary tangles) and neuromelanin-containing neurons in the substantia nigra (off-target binding). The lack of a consistent significant correlation between in vivo [F-18]-AV-1541 retention and postmortem in vitro binding and tau measures in these cases suggests that this ligand has low affinity for tau lesions primarily made of straight tau filaments. Interpretation AV-1451 may have limited utility for in vivo selective and reliable detection of tau aggregates in these non-Alzheimer tauopathies. ANN NEUROL 2017;81:117–128

Introduction Individuals with Down syndrome (DS) show enhanced amyloid beta (Aβ) deposition in the brain. A new positron emission tomography (PET) index of amyloid load (AβL) was recently developed as an alternative to standardized uptake value ratios (SUVrs) to quantify Aβ burden with high sensitivity for detecting and tracking Aβ change.1 Methods AβL was calculated in a DS cohort (N = 169, mean age ± SD = 39.6 ± 8.7 years) using [C‐11]Pittsburgh compound B (PiB) PET imaging. DS‐specific PiB templates were created for Aβ carrying capacity (K) and non‐specific binding (NS). Results The highest values of Aβ carrying capacity were found in the striatum and precuneus. Longitudinal changes in AβL displayed less variability when compared to SUVrs. Discussion These results highlight the utility of AβL for characterizing Aβ deposition in DS. Rates of Aβ accumulation in DS were found to be similar to that observed in late‐onset Alzheimer's disease (AD; ≈3% to 4% per year), suggesting that AD progression in DS is of earlier onset but not accelerated.

A blood test that predicts the extent of amyloid plaques in the brain and risk of Alzheimer’s disease would have important benefits for the early identification of higher risk of dementia and Alzheimer’s disease and the evaluation of new preventative therapies. The goal of this study was to determine whether plasma levels of amyloid-β1–42, 1–40 and the amyloid-β1–42/1–40 ratio among participants in the Pittsburgh centre of the Ginkgo Evaluation of Memory Study were related to the extent of brain fibrillar amyloid plaques measured in 2009 using Pittsburgh compound-B PET imaging, hippocampal volume, cortical thickness in the temporal lobe and white matter lesions. There were 194 participants who had Pittsburgh compound-B measurements in 2009 with the mean age of 85 years; 96% were white and 60% men. Pittsburgh compound-B positivity was defined as a standardized uptake value ratio of ≥1.57. Amyloid-β in blood was measured using a sandwich enzyme-linked immunosorbent assay developed by Eli Lilly and modified at the University of Vermont. All participants were nondemented as of 2008 at the time of study close out. The study sample included 160 with blood samples drawn in 2000–02 and 133 from 2009 and also had brain amyloid measured in 2009. All blood samples were analysed at the same time in 2009. Plasma amyloid-β1–42 was inversely related to the percent Pittsburgh compound-B positive (standardized uptake value ratio ≥1.57), β −0.04, P = 0.005. Practically all participants who were apolipoprotein-E4 positive at older ages were also Pittsburgh compound-B positive for fibrillar amyloid. Among apolipoprotein-E4-negative participants, quartiles of amyloid-β1–42 were inversely related to Pittsburgh compound-B positivity. In multiple regression models, plasma amyloid-β1–42 measured in 2000–02 or 2009 were significantly and inversely related to Pittsburgh compound-B positivity as was the amyloid-β1–42/1–40 ratio. There was a 4-fold increase in the odds ratio for the presence of Pittsburgh compound-B positivity in the brain in 2009 for the first quartile of amyloid-β1–42 as compared with the fourth quartile in the multiple logistic model. This is one of the first longitudinal studies to evaluate the relationship between amyloid-β1–42 in the blood and the extent of brain amyloid deposition measured by PET imaging using Pittsburgh compound-B. Our findings showed that remote and recent low plasma amyloid-β1–42 levels were inversely associated with brain amyloid deposition in cognitively normal individuals. However, changes in plasma amyloid-β1–42 over time (8 years) were small and not related to the amount of Pittsburgh compound-B., We have found an inverse relationship between plasma levels of amyloid-β1–42 in blood collected in 2000–02 (n = 160) and for same individuals in 2009 (n = 133) and amount of fibrillar amyloid measured by Pittsburgh compound-B in 2009. There was about a 4-fold higher risk of fibrillar amyloid for the first versus fourth quartile of amyloid-β1–42 in blood., Graphical Abstract Graphical Abstract