Brain Amyloid Accumulation Research Articles

Association of brain amyloid accumulation and glucose hypometabolism with cognition domain of language

AbstractBackgroundAmyloid is the main pathology for Alzheimer’s disease (AD), amyloid and glucose metabolism alternation are very important to investigate the progress of Alzheimer’s disease. However, not so many results were reported in Chinese population. In this study, we try to figure out the brain structure, function alternation and brain network alternation in Chinese subjective cognitive decline (SCD), mild cognition impairment (MCI) and Alzheimer’s disease (AD) from the data of Chinese preclinical Alzheimer’s disease (C‐PAS), which is initiated by us.Method200 participants were enrolled in this study, including 93 normal cognition (NC) healthy volunteers, 37 SCD, 34 MCI and 36 AD patients.6 types of neuropsychological tests from 3 cognitive domains and MMSE, Moca B were performed. FDG and amyloid PET (18F‐Flortabetapir) were conducted in these participants. 18F‐FDG and 18F‐Flortabetapir PET images were coregistered to the individual structural MRI images and then spatially normalized into MNI space.To assess the regional pattern of the 4 groups, one‐way ANOVA followed by two sample t test for post hoc analysis were performed, The statistical level was set at p<0.05 with FDR[hq1] correction and a minimum cluster extent Ke>20 voxels.ResultsIn Chinese population, changed glucosemetabolism were present in Superior temporalcortex, inferior temporal cortex, superior occipital cortex, precuneus, frontal cortex, supra‐marginal gyrus, anterior cingulate cortex, insula in a multiple comparison of AD MCI, SCD, and NC. And amyloid plaque were found in temporal cortex, frontal cortex, middle occipital cortex, inferior parietal cortex, insular, lingual gyrus, calcarine fissure and surrounding cortex, cingulate gyrus, fusiform gyrus, gyrus rectus, angular gyrus in these participants. Most of these changes were from AD patients, but slight hypometabolism, and amyloid accumulation were found among NC, SCD, MCI.ConclusionCortex and cingulate gyrus were the main regions for amyloid accumulation and glucose hypometabolism for Chinese AD patients. However, slight change was observed in NC, SCD, MCI participants.

AHEAD 3‐45 study design: A global study to evaluate the efficacy and safety of treatment with BAN2401 for 216 weeks in preclinical Alzheimer’s disease with intermediate amyloid (A3 trial) and elevated amyloid (A45 trial)

AbstractBackgroundAβ pathologies occur years prior to cortical tauopathy, neurodegeneration, and clinical symptoms. BAN2401 is a humanized immunoglobulin G1 monoclonal antibody that selectively binds to soluble Aβ aggregated species (oligomers, protofibrils). BAN2401 reduced amyloid on PET and slowed cognitive decline in a Phase 2 study in early symptomatic AD. The AHEAD 3‐45 study will test the safety and efficacy of BAN2401 even earlier in the AD continuum.MethodAHEAD 3‐45 consists of two trials (A3 Trial and A45 Trial) under a single protocol and screening process, common schedule of assessments, and distinct dosing regimens tailored to the baseline amyloid level. The study is a Public‐Private Partnership of the Alzheimer’s Clinical Trial Consortium (ACTC), National Institutes of Health (NIH), and Eisai, Inc. The A3 Trial will enroll cognitively normal individuals (CN) with intermediate amyloid (approximately 20‐40 centiloids), at risk for further amyloid accumulation and development of neurofibrillary tangles on tau PET over four years. Approximately 400 participants will be randomized 1:1 to placebo or BAN2401 infusion—8 weeks of titration followed by 10 mg/kg every four weeks for 216 weeks. The A45 Trial will enroll CN individuals with elevated amyloid, defined as amyloid PET approximately >40 centiloids, at risk for cognitive decline over four years. Approximately 1000 participants will be randomized 1:1 to placebo or BAN2401 infusion—8 weeks of biweekly titration dosing, then 10 mg/kg biweekly induction dosing through 96 weeks to clear aggregated Ab, followed by 10 mg/kg every four weeks maintenance dosing through 216 weeks to prevent reaccumulation of Aβ.ResultLongitudinal cognitive, safety, amyloid and tau PET, MRI and fluid biomarker assessments will be performed. The primary outcome of the A3 Trial is prevention of brain amyloid accumulation by amyloid PET at 216 weeks, with delay of tau PET accumulation as a key secondary outcome. The primary outcome measure of the A45 Trial is the Preclinical Alzheimer’s Disease Cognitive Composite 5 (PACC5) scale at 216 weeks.ConclusionThe AHEAD 3‐45 Study will test whether BAN2401 can prevent the accumulation and spread of Aβ deposition, downstream tau pathology, and cognitive decline in at‐risk cognitively normal individuals prior to significant irreversible neurodegeneration.

Association of brain amyloid accumulation and glucose hypometabolism with memory loss

AbstractBackgroundMemory loss is the main syndrome of Alzheimer’s disease (AD). Extracellular accumulation of amyloid‐β (Aβ) neuritic plaques and neurodegeneration such as glucose hypometabolismwere the main pathology of AD. In this study, we try to figure out the association of Aβ accumulation and glucose hypometabolism with memory loss.Methods91 normal cognition (NC) healthy volunteers, 37 subjective cognitive decline (SCD), 32 mild cognition impairment (MCI) and 34 AD patients were enrolled in this study from Chinese preclinical Alzheimer’s disease (C‐PAS), which is initiated by Shanghai Jiao Tong University Affiliated Sixth People’s Hospital and Huashan Hospital. 6 types of neuropsychological tests from 3 cognitive core, including Auditory verbal learning test (AVLT) 30‐minute delayed free recall and AVLT recognition for memory, MMSE, Moca B were performed. FDG and amyloid PET (18F‐Flortabetapir) were conducted in these participants. 18F‐FDG and 18F‐Flortabetapir PET images were coregistered to the individual structural MRI images and then spatially normalized into MNI space. The associations of FDG and Aβ with impairment of language were explored by performing multiple regression between the 18F‐FDG and neuropsychological scores, as well as 18F‐Flortabetapir PET images and neuropsychological scores with age, gender, educationalyears as covariates. The statistical level was set at p<0.05 with FDR correction and a minimum cluster extent Ke>20 voxels.ResultsNo relationship was found between memory loss and amyloid accumulation. Glucose metabolism in precuneus, middle frontal cortex, cuneus, posterior cingulate gyrus has association with AVLT 30‐minute delayed free recall. Association was observed between glucose metabolism in inferior frontal cortex, insula and AVLT recognition.ConclusionAssociations were observed between memory loss and glucose hypometabolism, but no association was found between amyloid and memory loss.

Structural Diversity of Co(II) Coordination Polymers: Treatment Activity on Alzheimer’s Disease Via Reducing the Accumulation of Amyloid in Brain

Two novel coordination polymers (CPs) based on Co(II) ions as nodes with the chemical formula of {Co(DBTA)(phen)(H2O)}n (1) (phen = 1,10-Phenanthroline and H2DBTA = 2,5-Dibromo-terephthalic acid) and [Co(DBTA)(bimb)]n (2) (bimb = 1,4-bis(imidazole-1-ylmethyl)benzene) were prepared via Co(NO3)2·6H2O reacting with the H2DBTA in the existence of distinct nitrogen-donor co-ligands (phen for the complex 1 and bimb for the complex 2) under solvothermal conditions. Compounds 1 and 2 with novel structures were evaluated for Alzheimer’s disease (AD) treatment. Serious experiments were performed and the specific mechanism for compound also was investigated. Firstly, the AD animal model was constructed in the mice, then we injected the compound 1 or 2 into mice to perform the indicated treatment at 5 mg/kg concentration. After that, the brain volume and brain weight were measured. Then, the Amyloid (Aβ) content in cerebrospinal fluid was determined to assess the activity of compound. The inflammatory cytokines released into the cerebrospinal fluid was also determined with enzyme linked immunosorbent assay (ELISA) detection. Finally, the reactive oxygen species (ROS) accumulation in the cerebral cortex cells was detected.

Spatiotemporal relationship between subthreshold amyloid accumulation and aerobic glycolysis in the human brain

In Alzheimer's disease, brain amyloid deposition has a distinct topography that correlates with aerobic glycolysis (AG), that is, the use of glucose beyond that predicted by oxygen consumption. The causes for this relationship remain unclear but might provide crucialinsight into how amyloid deposition begins. Here we develop methods to study the earliest topography of amyloid deposition based on amyloid imaging and investigate its spatiotemporal evolution with respect to the topography of AG in adults. We find that the spatiotemporal dynamics of amyloid deposition are largely explained by 1 factor, defined here as the amyloid topography dissimilarity index (ATDI). ATDI is bimodal, more highly dynamic during early amyloid accumulation, and predicts which individuals will cross a conservative quantitative threshold at least 3–5 years in advance. Using ATDI, we demonstrate that subthreshold amyloid accumulates primarily in regions that have high AG during early adulthood. Our findings suggest that early on-target subthreshold amyloid deposition mirrors its later regional pattern, which best corresponds to the topography of young adult brain AG.

High-Density Lipoprotein Mimetic Peptide 4F Efficiently Crosses the Blood-Brain Barrier and Modulates Amyloid-β Distribution between Brain and Plasma.

Treatments to elevate high-density lipoprotein (HDL) levels in plasma have decreased cerebrovascular amyloid -β (Aβ) deposition and mitigated cognitive decline in Alzheimer disease (AD) transgenic mice. Since the major protein component of HDL particles, apolipoprotein A-I (ApoA-I), has very low permeability at the blood-brain barrier (BBB), we investigated 4F, an 18-amino-acid ApoA-I/HDL mimetic peptide, as a therapeutic alternative. Specifically, we examined the BBB permeability of 4F and its effects on [125I]Aβ trafficking from brain to blood and from blood to brain. After systemic injection in mice, the BBB permeability of [125I]4F, estimated as the permeability-surface area (PS) product, ranged between 2 and 5 × 10-6 ml/g per second in various brain regions. The PS products of [125I]4F were ∼1000-fold higher compared with those determined for [125I]ApoA-I. Moreover, systemic infusion with 4F increased the brain efflux of intracerebrally injected [125I]Aβ42. Conversely, 4F infusion decreased the brain influx of systemically injected [125I]Aβ42. Interestingly, 4F did not significantly alter the brain influx of [125I]Aβ40. To corroborate the in vivo findings, we evaluated the effects of 4F on [125I]Aβ42 transcytosis across polarized human BBB endothelial cell (hCMEC/D3) monolayers. Treatment with 4F increased the abluminal-to-luminal flux and decreased the luminal-to-abluminal flux of [125I]Aβ42 across the hCMEC/D3 monolayers. Additionally, 4F decreased the endothelial accumulation of fluorescein-labeled Aβ42 in the hCMEC/D3 monolayers. These findings provide a mechanistic interpretation for the reductions in brain Aβ burden reported in AD mice after oral 4F administration, which represents a novel strategy for treating AD and cerebral amyloid angiopathy. SIGNIFICANCE STATEMENT: The brain permeability of the ApoA-I mimetic peptide 4F was estimated to be ∼1000-fold greater than ApoA-I after systemic injection of radiolabeled peptide/protein in mice. Further, 4F treatment increased the brain efflux of amyloid -β and also decreased its brain influx, as evaluated in mice and in blood-brain barrier cell monolayers. Thus, 4F represents a potential therapeutic strategy to mitigate brain amyloid accumulation in cerebral amyloid angiopathy and Alzheimer disease.

Hippocampal Volume Loss, Brain Amyloid Accumulation, and APOE Status in Cognitively Intact Elderly Subjects

Background: Hippocampal volume loss (HVL), PET-documented brain amyloid accumulation, and APOE-ε4 status are predictive biomarkers of the transition from mild cognitive impairment to Alzheimer disease (AD). In asymptomatic cases, the role of these biomarkers remains ambiguous. In contrast to the idea that HVL occurs in late phases of neurodegeneration, recent contributions indicate that it might occur before abnormal amyloid PET occurrence in elderly subjects and that its severity could be only marginally related to APOE variants. Using a longitudinal design, we examined the determinants of HVL in our sample, i.e., brain amyloid burden and the presence of APOE-ε4, and made a longitudinal assessment of cognitive functions. Methods: We performed a 4.5-year longitudinal study on 81 elderly community dwellers (all right-handed;, 48 (59.3%) women; mean age 73.7 ± 3.7 years) including MRI at baseline and follow-up, PET amyloid during follow-up, neuropsychological assessment at 18 and 54 months, and APOE genotyping. All cases were assessed using a continuous cognitive score (CCS) that took into account the global evolution of neuropsychological performance. Linear regression models were used to identify predictors of HVL. Results: There was a negative association between the CCS and HVL bilaterally. In multivariate models adjusting for demographic variables, the presence of APOE-ε4 was related to increased HVL bilaterally. A trend of significance was observed with respect to the impact of amyloid positivity on HVL in the left hemisphere. No significant interaction was found between amyloid positivity and the APOE-ε4 allele. Conclusion: The progressive decrement of neuropsychological performance is associated with HVL long before the emergence of clinically overt symptoms. In this cohort of healthy individuals, the presence of the APOE-ε4 allele was shown to be an independent predictor of worst hippocampal integrity in asymptomatic cases independently of amyloid positivity.

Association between brain amyloid accumulation and neuropsychological characteristics in elders with depression and mild cognitive impairment.

To investigate the presence of cerebral amyloidopathy and its associations with performances on neurocognitive tests and clinical features in depressed elders with mild cognitive impairment (MCI). In total, 94 older adults with concomitant MCI and some depressive symptoms were included in this study. Cerebral amyloidopathy was evaluated using 18 F-florbetaben-positron emission tomography. A standardized neurocognitive test battery and brain magnetic resonance imaging (MRI) were administered to all subjects. We examined the Apolipoprotein E genotype using a polymerase chain reaction-based method. Among the 94 initial participants, seven participants were excluded because of failure to undergo MRI or complete the neuropsychological battery. Among 87 subjects, 45 elders (51.7%) had cerebral amyloidopathy and were classified as the concomitant depression and MCI with cerebral amyloid-accumulation-positive (CDAP) group; others were classified as the concomitant depression and MCI with cerebral amyloid-accumulation-negative (CDAN) group. Poorer performances on word list recall and constructional recall were observed in the CDAP group than in the CDAN group. The results indicate that around half of older adults with concomitant MCI and some depressive symptoms might be prone to have Alzheimer dementia. Results of neurocognitive tests possibly aid in discerning the presence of cerebral amyloidopathy.

Sleep-Cognition Hypothesis In maritime Pilots, what is the effect of long-term work-related poor sleep on cognition and amyloid accumulation in healthy middle-aged maritime pilots: methodology of a case–control study

IntroductionEvidence indicates a bidirectional relationship between poor sleep and Alzheimer’s disease (AD). While AD may lead to disruption of normal sleep, poor sleep in itself may play a causal role...

Emerging cerebrospinal fluid biomarkers in autosomal dominant Alzheimer's disease

IntroductionFour less well-studied but promising “emerging” cerebrospinal fluid (CSF) biomarkers are elevated in late-onset Alzheimer disease (AD): neurogranin, synaptosomal-associated protein-25 (SNAP-25), visinin-like protein 1 (VILIP-1), and chitinase-3-like protein 1 (YKL-40). MethodsCSF neurogranin, SNAP-25, VILIP-1, and YKL-40 were measured in families carrying autosomal-dominant AD mutations. ResultsThe four emerging CSF biomarkers were significantly elevated in the mutation carriers (n = 235) versus noncarriers (n = 145). CSF SNAP-25, VILIP-1, and YKL-40 were altered very early in the AD time course, approximately 15–19 years before estimated symptom onset. All CSF biomarkers predicted important AD-related outcomes including performance on a cognitive composite, brain amyloid burden as measured by amyloid positron emission tomography, and the estimated years from symptom onset. DiscussionEarly abnormalities in CSF tTau, pTau, SNAP-25, VILIP-1, and YKL-40 suggest that synaptic damage, neuronal injury, and neuroinflammation begin shortly after the commencement of brain amyloid accumulation.

PKR knockout in the 5xFAD model of Alzheimer's disease reveals beneficial effects on spatial memory and brain lesions.

Brain lesions in Alzheimer's disease (AD) include amyloid plaques made of Aβ peptides and neurofibrillary tangles composed of hyperphosphorylated tau protein with synaptic and neuronal loss and neuroinflammation. Aβ oligomers can trigger tau phosphorylation and neuronal alterations through activation of neuronal kinases leading to progressive cognitive decline. PKR is a ubiquitous pro‐apoptotic serine/threonine kinase, and levels of activated PKR are increased in AD brains and AD CSF. In addition, PKR regulates negatively memory formation in mice. To assess the role of PKR in an AD in vivo model, we crossed 5xFAD transgenic mice with PKR knockout (PKRKO) mice and we explored the contribution of PKR on cognition and brain lesions in the 5xFAD mouse model of AD as well as in neuron–microglia co‐cultures exposed to the innate immunity activator lipopolysaccharide (LPS). Nine‐month‐old double‐mutant mice revealed significantly improved memory consolidation with the new object location test, starmaze test, and elevated plus maze test as compared to 5xFAD mice. Brain amyloid accumulation and BACE1 levels were statistically decreased in double‐mutant mice. Apoptosis, neurodegeneration markers, and synaptic alterations were significantly reduced in double‐mutant mice as well as neuroinflammation markers such as microglial load and brain cytokine levels. Using cocultures, we found that PKR in neurons was essential for LPS microglia‐induced neuronal death. Our results demonstrate the clear involvement of PKR in abnormal spatial memory and brain lesions in the 5xFAD model and underline its interest as a target for neuroprotection in AD.

A longitudinal multimodal in vivo molecular imaging study of the 3xTg-AD mouse model shows progressive early hippocampal and taurine loss.

The understanding of the natural history of Alzheimer’s disease (AD) and temporal trajectories of in vivo molecular mechanisms requires longitudinal approaches. A behavioral and multimodal imaging study was performed at 4/8/12 and 16 months of age in a triple transgenic mouse model of AD (3xTg-AD). Behavioral assessment included the open field and novel object recognition tests. Molecular characterization evaluated hippocampal levels of amyloid β (Aβ) and hyperphosphorylated tau. Magnetic resonance imaging (MRI) included assessment of hippocampal structural integrity, blood–brain barrier (BBB) permeability and neurospectroscopy to determine levels of the endogenous neuroprotector taurine. Longitudinal brain amyloid accumulation was assessed using 11C Pittsburgh compound B positron emission tomography (PET), and neuroinflammation/microglia activation was investigated using 11C-PK1195. We found altered locomotor activity at months 4/8 and 16 months and recognition memory impairment at all time points. Substantial early reduction of hippocampal volume started at month 4 and progressed over 8/12 and 16 months. Hippocampal taurine levels were significantly decreased in the hippocampus at months 4/8 and 16. No differences were found for amyloid and neuroinflammation with PET, and BBB was disrupted only at month 16. In summary, 3xTg-AD mice showed exploratory and recognition memory impairments, early hippocampal structural loss, increased Aβ and hyperphosphorylated tau and decreased levels of taurine. In sum, the 3xTg-AD animal model mimics pathological and neurobehavioral features of AD, with early-onset recognition memory loss and MRI-documented hippocampal damage. The early-onset profile suggests temporal windows and opportunities for therapeutic intervention, targeting endogenous neuroprotectors such as taurine.

Metabolic Syndrome and Amyloid Accumulation in the Aging Brain.

Recent studies show links between metabolic syndrome and Alzheimer's disease (AD) neuropathology. Understanding the link between vascular-related health conditions and dementia will help target at risk populations and inform clinical strategies for early detection and prevention of AD. To determine whether metabolic syndrome is associated with global cerebral amyloid-β (Aβ) positivity and longitudinal Aβ accumulation. Prospective study of 165 participants who underwent (11)C-Pittsburgh compound B (PiB) PET neuroimaging to measure Aβ, from June 2005 to May 2016. Metabolic syndrome was defined using the revised Third Adults Treatment Panel of the National Cholesterol Education Program criteria. Participants were classified as PiB+/-. Linear mixed effects models assessed the relationships between baseline metabolic syndrome and PiB status and regional Aβ change over time. A total of 165 cognitively normal participants of the Baltimore Longitudinal Study of Aging (BLSA) Neuroimaging substudy, aged 55-92 years (mean baseline age = 76.4 years, 85 participants were male), received an average of 2.5 PET-PiB scans over an average interval of 2.6 (3.08 SD) years between first and last visits. Metabolic syndrome was not associated with baseline PiB positivity or concurrent regional Aβ. Metabolic syndrome was associated with increased rates of Aβ accumulation in superior parietal and precuneus regions over time in the PiB+ group. Elevated fasting glucose and blood pressure showed individual associations with accelerated Aβ accumulation. Metabolic syndrome was associated with accelerated Aβ accumulation in PiB+ individuals and may be an important factor in the progression of AD pathology.

Midlife insulin resistance, APOE genotype, and late-life brain amyloid accumulation.

ObjectiveTo examine whether midlife insulin resistance is an independent risk factor for brain amyloid accumulation in vivo after 15 years, and whether this risk is modulated by APOE ε4 genotype.MethodsThis observational study examined 60 elderly volunteers without dementia (mean age at baseline 55.4 and at follow-up 70.9 years, 55.5% women) from the Finnish population-based, nationwide Health2000 study with [11C]Pittsburgh compound B–PET imaging in 2014–2016. The participants were recruited according to their homeostatic model assessment of insulin resistance (HOMA-IR) values in the year 2000, and their APOE ε4 genotype. The exposure group (IR+, n = 30) consisted of individuals with HOMA-IR >2.17 at baseline (highest tertile of the Health2000 study population), and the control group (IR−, n = 30) consisted of individuals with HOMA-IR <1.25 at baseline (lowest tertile). The groups were enriched for APOE ε4 carriers, resulting in 50% (n = 15) APOE ε4 carriers in both groups. Analyses were performed with multivariate logistic and linear regression.ResultsAn amyloid-positive PET scan was found in 33.3% of the IR− group and 60.0% of the IR+ group (odds ratio 3.0, 95% confidence interval 1.1–8.9, p = 0.04). The increased risk was seen in carriers and noncarriers of APOE ε4 genotype. Higher midlife, but not late-life continuous HOMA-IR was associated with a greater brain amyloid burden at follow-up after multivariate adjustments for other cognitive and metabolic risk factors (β = 0.11, 95% confidence interval 0.002–0.22, p = 0.04).ConclusionsThese results indicate that midlife insulin resistance is an independent risk factor for brain amyloid accumulation in elderly individuals without dementia.

Brain amyloid load and its associations with cognition and vascular risk factors in FINGER Study.

To investigate brain amyloid pathology in a dementia-risk population defined as cardiovascular risk factors, aging, and dementia risk (CAIDE) score of at least 6 but with normal cognition and to examine associations between brain amyloid load and cognitive performance and vascular risk factors. A subgroup of 48 individuals from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) main study participated in brain 11C-Pittsburgh compound B (PiB)-PET imaging, brain MRI, and neuropsychological assessment at the beginning of the study. Lifestyle/vascular risk factors were determined as body mass index, blood pressure, total and low-density lipoprotein cholesterol, and glucose homeostasis model assessment. White matter lesions were visually rated from MRIs by a semiquantitative Fazekas score. Twenty participants (42%) had a positive PiB-PET on visual analysis. The PiB-positive group performed worse in executive functioning tests, included more participants with APOE ε4 allele (50%), and showed slightly better glucose homeostasis compared to PiB-negative participants. PiB-positive and -negative participants did not differ significantly in other cognitive domain scores or other vascular risk factors. There was no significant difference in Fazekas score between the PiB groups. The high percentage of PiB-positive participants provides evidence of a successful recruitment process of the at-risk population in the main FINGER intervention trial. The results suggest a possible association between early brain amyloid accumulation and decline in executive functions. APOE ε4 was clearly associated with amyloid positivity, but no other risk factor was found to be associated with positive PiB-PET.

Memory and Brain Amyloid and Tau Effects of a Bioavailable Form of Curcumin in Non-Demented Adults: A Double-Blind, Placebo-Controlled 18-Month Trial

Because curcumin's anti-inflammatory properties may protect the brain from neurodegeneration, we studied its effect on memory in non-demented adults and explored its impact on brain amyloid and tau accumulation using 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile positron emission tomography (FDDNP-PET). Forty subjects (age 51-84 years) were randomized to a bioavailable form of curcumin (Theracurmin® containing 90 mg of curcumin twice daily [N = 21]) or placebo (N = 19) for 18 months. Primary outcomes were verbal (Buschke Selective Reminding Test [SRT]) and visual (Brief Visual Memory Test-Revised [BVMT-R]) memory, and attention (Trail Making A) was a secondary outcome. FDDNP-PET signals (15 curcumin, 15 placebo) were determined in amygdala, hypothalamus, medial and lateral temporal, posterior cingulate, parietal, frontal, and motor (reference) regions. Mixed effects general linear models controlling for age and education, and effect sizes (ES; Cohen's d) were estimated. SRT Consistent Long-Term Retrieval improved with curcumin (ES = 0.63, p = 0.002) but not with placebo (ES = 0.06, p = 0.8; between-group: ES = 0.68, p = 0.05). Curcumin also improved SRT Total (ES = 0.53, p = 0.002), visual memory (BVMT-R Recall: ES = 0.50, p = 0.01; BVMT-R Delay: ES = 0.51, p = 0.006), and attention (ES = 0.96, p < 0.0001) compared with placebo (ES = 0.28, p = 0.1; between-group: ES = 0.67, p = 0.04). FDDNP binding decreased significantly in the amygdala with curcumin (ES = -0.41, p = 0.04) compared with placebo (ES = 0.08, p = 0.6; between-group: ES = 0.48, p = 0.07). In the hypothalamus, FDDNP binding did not change with curcumin (ES = -0.30, p = 0.2), but increased with placebo (ES = 0.26, p = 0.05; between-group: ES = 0.55, p = 0.02). Daily oral Theracurmin may lead to improved memory and attention in non-demented adults. The FDDNP-PET findings suggest that symptom benefits are associated with decreases in amyloid and tau accumulation in brain regions modulating mood and memory.

Weighting and standardization of frequencies to determine prevalence of AD imaging biomarkers.

To estimate the prevalence of elevated brain amyloid and reduced cortical thickness (as a marker for neurodegeneration) in a defined population. Mayo Clinic Study of Aging participants underwent MRI to assess a composite Alzheimer disease (AD) signature cortical thickness measure and PET to assess brain amyloid accumulation. Participants were characterized as having elevated amyloid (A+/A-), reduced cortical thickness (N+/N-), and A+N+, A+N-, A-N+, or A-N-. The prevalence of AD biomarkers was derived by adjusting for nonparticipation and standardizing to the Olmsted County, Minnesota, population. Among 1,646 participants without dementia (mean age 70.8 years; 53.2% men), the prevalence (95% confidence interval) of amyloidosis was 21.1% (19.1%-23.2%): women, 24.3%; men, 17.5%. The prevalence of reduced cortical thickness was 28.9% (26.4%-31.5%): women, 27.9%; men, 30.2%. The prevalence estimates of biomarker categories were as follows: A-N-: 61.4%; A+N-: 9.7%; A-N+: 17.4%; and A+N+: 11.5%, and varied by sex and by APOE ε4 carrier status. In men, prevalence estimates were as follows: A-N-: 62.6%; A+N-: 7.3%; A-N+: 19.9%; and A+N+: 10.2%. In women, prevalence estimates were as follows: A-N-: 60.4%; A+N-: 11.7%; A-N+: 15.3%; and A+N+: 12.6%. In ε4 carriers, prevalence estimates were as follows: A-N-: 54.6%; A+N-: 16.6%; A-N+: 12.4%; and A+N+: 16.4%. In non-ε4 carriers, prevalence estimates were as follows: A-N-: 63.3%; A+N-: 6.9%; A-N+: 19.9%; and A+N+: 10.0%. These prevalence estimates are important for understanding age-related trends in amyloid positivity and AD signature cortical thickness in the population, and for potentially projecting the future burden of biomarkers in elderly persons.

Brain glucose metabolism and its relation to amyloid load in middle-aged adults with childhood-onset epilepsy

Uncomplicated childhood-onset epilepsy is associated with increased brain amyloid load at late middle age, but its possible association with Alzheimer-type neurodegenerative processes is unclear. After 50-year follow-up, 42 childhood onset epilepsy subjects and 45 matched controls were investigated with [18F]fluorodeoxyglucose PET. There were no significant differences between the subjects and controls, but higher [18F]fluorodeoxyglucose uptake was associated with a higher local amyloid load (as measured with [11C]PIB PET) in the prefrontal cortex, parietal cortex, and posterior cingulate/precuneus in subjects but not in controls. These findings parallel reported observations in cognitively normal individuals with increased brain amyloid accumulation who are at risk for future Alzheimer’s disease.

Associations of CAIDE Dementia Risk Score with MRI, PIB-PET measures, andcognition.

Background:CAIDE Dementia Risk Score is the first validated tool for estimating dementia risk based on a midlife risk profile.Objectives:This observational study investigated longitudinal associations of CAIDE Dementia Risk Score with brain MRI, amyloid burden evaluated with PIB-PET, and detailed cognition measures.Methods:FINGER participants were at-risk elderly without dementia. CAIDE Risk Score was calculated using data from previous national surveys (mean age 52.4 years). In connection to baseline FINGER visit (on average 17.6 years later, mean age 70.1 years), 132 participants underwent MRI scans, and 48 underwent PIB-PET scans. All 1,260 participants were cognitively assessed (Neuropsychological Test Battery, NTB). Neuroimaging assessments included brain cortical thickness and volumes (Freesurfer 5.0.3), visually rated medial temporal atrophy (MTA), white matter lesions (WML), and amyloid accumulation.Results:Higher CAIDE Dementia Risk Score was related to more pronounced deep WML (OR 1.22, 95% CI 1.05–1.43), lower total gray matter (β-coefficient –0.29, p = 0.001) and hippocampal volume (β-coefficient –0.28, p = 0.003), lower cortical thickness (β-coefficient –0.19, p = 0.042), and poorer cognition (β-coefficients –0.31 for total NTB score, –0.25 for executive functioning, –0.33 for processing speed, and –0.20 for memory, all p < 0.001). Higher CAIDE Dementia Risk Score including APOE genotype was additionally related to more pronounced MTA (OR 1.15, 95% CI 1.00–1.30). No associations were found with periventricular WML or amyloid accumulation.Conclusions:The CAIDE Dementia Risk Score was related to indicators of cerebrovascular changes and neurodegeneration on MRI, and cognition. The lack of association with brain amyloid accumulation needs to be verified in studies with larger sample sizes.

‘Type 3’ diabetes: a brain insulin‐resistant state linked to Alzheimer's disease

‘Type 3’ diabetes: a brain insulin‐resistant state linked to Alzheimer's disease