Cerebral Amyloid-β Research Articles

Sequence of Alzheimer disease biomarker changes in cognitively normal adults: A cross-sectional study.

To determine the ordering of changes in Alzheimer disease (AD) biomarkers among cognitively normal individuals. Cross-sectional data, including CSF analytes, molecular imaging of cerebral fibrillar β-amyloid (Aβ) with PET using the [11C] benzothiazole tracer Pittsburgh compound B (PiB), MRI-based brain structures, and clinical/cognitive outcomes harmonized from 8 studies, collectively involving 3,284 cognitively normal individuals 18 to 101 years of age, were analyzed. The age at which each marker exhibited an accelerated change (called the change point) was estimated and compared across the markers. Accelerated changes in CSF Aβ1-42 (Aβ42) occurred at 48.28 years of age and in Aβ42/Aβ40 ratio at 46.02 years, followed by PiB mean cortical standardized uptake value ratio (SUVR) with a change point at 54.47 years. CSF total tau (Tau) and tau phosphorylated at threonine 181 (Ptau) had a change point at ≈60 years, similar to those for MRI hippocampal volume and cortical thickness. The change point for a cognitive composite occurred at 62.41 years. The change points for CSF Aβ42 and Aβ42/Aβ40 ratio, albeit not significantly different from that for PiB SUVR, occurred significantly earlier than that for CSF Tau, Ptau, MRI markers, and the cognitive composite. Adjusted analyses confirmed that accelerated changes in CSF Tau, Ptau, MRI markers, and the cognitive composite occurred at ages not significantly different from each other. Our findings support the hypothesized early changes of amyloid in preclinical AD and suggest that changes in neuronal injury and neurodegeneration markers occur close in time to cognitive decline.

GSK3‐ARC/Arg3.1 and GSK3‐Wnt signaling axes trigger amyloid‐β accumulation and neuroinflammation in middle‐aged Shugoshin 1 mice

The cerebral amyloid‐β accumulation that begins in middle age is considered the critical triggering event in the pathogenesis of late‐onset Alzheimer's disease (LOAD). However, the molecular mechanism remains elusive. The Shugoshin 1 (Sgo1−/+) mouse model, a model for mitotic cohesinopathy‐genomic instability that is observed in human AD at a higher rate, showed spontaneous accumulation of amyloid‐β in the brain at old age. With the model, novel insights into the molecular mechanism of LOAD development are anticipated. In this study, the initial appearance of cerebral amyloid‐β accumulation was determined as 15‐18 months of age (late middle age) in the Sgo1−/+ model. The amyloid‐β accumulation was associated with unexpected GSK3α/β inactivation, Wnt signaling activation, and ARC/Arg3.1 accumulation, suggesting involvement of both the GSK3‐Arc/Arg3.1 axis and the GSK3‐Wnt axis. As observed in human AD brains, neuroinflammation with IFN‐γ expression occurred with amyloid‐β accumulation and was pronounced in the aged (24‐month‐old) Sgo1−/+ model mice. AD‐relevant protein panels (oxidative stress defense, mitochondrial energy metabolism, and β‐oxidation and peroxisome) analysis indicated (a) early increases in Pdk1 and Phb in middle‐aged Sgo1−/+ brains, and (b) misregulations in 32 proteins among 130 proteins tested in old age. Thus, initial amyloid‐β accumulation in the Sgo1−/+ model is suggested to be triggered by GSK3 inactivation and the resulting Wnt activation and ARC/Arg3.1 accumulation. The model displayed characteristics and affected pathways similar to those of human LOAD including neuroinflammation, demonstrating its potential as a study tool for the LOAD development mechanism and for preclinical AD drug research and development.

Determining Amyloid-β Positivity Using 18F-AZD4694 PET Imaging.

Amyloid-β deposition into plaques is a pathologic hallmark of Alzheimer disease appearing years before the onset of symptoms. Although cerebral amyloid-β deposition occurs on a continuum, dichotomization into positive and negative groups has advantages for diagnosis, clinical management, and population enrichment for clinical trials. 18F-AZD4694 (also known as 18F-NAV4694) is an amyloid-β imaging ligand with high affinity for amyloid-β plaques. Despite being used in multiple academic centers, no studies have assessed a quantitative cutoff for amyloid-β positivity using 18F-AZD4694 PET. Methods: We assessed 176 individuals [young adults (n = 22), cognitively unimpaired elderly (n = 89), and cognitively impaired (n = 65)] who underwent amyloid-β PET with 18F-AZD4694, lumbar puncture, structural MRI, and genotyping for APOEε418F-AZD4694 values were normalized using the cerebellar gray matter as a reference region. We compared 5 methods for deriving a quantitative threshold for 18F-AZD4694 PET positivity: comparison with young-control SUV ratios (SUVRs), receiver-operating-characteristic (ROC) curves based on clinical classification of cognitively unimpaired elderly versus Alzheimer disease dementia, ROC curves based on visual Aβ-positive/Aβ-negative classification, gaussian mixture modeling, and comparison with cerebrospinal fluid measures of amyloid-β, specifically the Aβ42/Aβ40 ratio. Results: We observed good convergence among the 4 methods: ROC curves based on visual classification (optimal cut point, 1.55 SUVR), ROC curves based on clinical classification (optimal cut point, 1.56 SUVR) gaussian mixture modeling (optimal cut point, 1.55 SUVR), and comparison with cerebrospinal fluid measures of amyloid-β (optimal cut point, 1.51 SUVR). Means and 2 SDs from young controls resulted in a lower threshold (1.33 SUVR) that did not agree with the other methods and labeled most elderly individuals as Aβ-positive. Conclusion: Good convergence was obtained among several methods for determining an optimal cutoff for 18F-AZD4694 PET positivity. Despite conceptual and analytic idiosyncrasies linked with dichotomization of continuous variables, an 18F-AZD4694 threshold of 1.55 SUVR had reliable discriminative accuracy. Although clinical use of amyloid PET is currently by visual inspection of scans, quantitative thresholds may be helpful to arbitrate disagreement among raters or in borderline cases.

Serum albumin and beta-amyloid deposition in the human brain.

ObjectivesTo investigate the relationships of serum albumin with in vivo Alzheimer disease (AD) pathologies, including cerebral β-amyloid (Aβ) protein deposition, neurodegeneration of AD-signature regions, and cerebral white matter hyperintensities (WMH), in the human brain.MethodsA total of 396 older adults without dementia underwent comprehensive clinical assessments, measurement of serum albumin level, and multimodal brain imaging, including [11C] Pittsburgh compound B-PET, 18F-fluorodeoxyglucose-PET, and MRI. Serum albumin was categorized as follows: <4.4 g/dL (low albumin), 4.4 to 4.5 g/dL (middle albumin), and >4.5 g/dL (high albumin; used as a reference category). Aβ positivity, AD-signature region cerebral glucose metabolism (AD-CM), AD-signature region cortical thickness (AD-CT), and WMH volume were used as outcome measures.ResultsSerum albumin level (as a continuous variable) was inversely associated with Aβ deposition and Aβ positivity. The low albumin group showed a significantly higher Aβ positivity rate compared to the high albumin group (odds ratio 3.40, 95% confidence interval 1.67–6.92, p = 0.001), while the middle albumin group showed no difference (odds ratio 1.74, 95% confidence interval 0.80–3.77, p = 0.162). Neither serum albumin level (as a continuous variable) nor albumin categories were related to AD-CM, AD-CT, or WMH volume.ConclusionsLow serum albumin may increase the risk of AD dementia by elevating amyloid accumulation. In terms of AD prevention, more attention needs to be paid to avoid a low serum albumin level, even within the clinical normal range, by clinicians.

Sex-Specific Association of Lifetime Body Mass Index with Alzheimer's Disease Neuroimaging Biomarkers.

Background:Although recent studies indicate that the relationship between body mass index (BMI) and Alzheimer’s disease (AD) may differ by both sex and age of BMI measurement, little information is available on sex- or age-specific associations between BMI and AD neuropathologies.Objective:To examined whether sex-specific BMIs measured at different life-stages (in early adulthood, midlife, and late life) were associated with cerebral amyloid-β (Aβ) deposition and AD-signature region cortical thickness (AD-CT) in cognitively normal (CN) older adults.Methods:A total of 212 CN subjects aged 60–90 years (females 108, males 104), who participated in the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE), an ongoing prospective cohort study, were included. All participants underwent comprehensive clinical and neuropsychological assessments, [11C] Pittsburgh Compound B positron emission tomography, and brain magnetic resonance imaging. BMIs at different life stages were calculated. Multiple regression analyses were performed separately for either sex.Results:In males, lower early adulthood or midlife BMI was associated with greater cerebral Aβ deposition, but late life BMI was not. Lower midlife BMI was associated with reduced AD-CT, but the BMI in early adulthood and late life was not. In females, no significant association was observed between any lifetime BMI and Aβ deposition or AD-CT.Conclusion:Our results support a male-specific association between BMI prior to late life, and in vivo AD pathologies. Avoiding underweight status early in life may be important to prevent AD dementia in males, but not females.

Amyloid PET in Dementia Syndromes: A Chinese Multicenter Study.

Cerebral β-amyloid deposits and regional glucose metabolism assessed by PET are used to distinguish between Alzheimer disease (AD) and other dementia syndromes. In the present multicenter study, we estimated the prevalence of β-amyloid deposits on PET imaging in a wide variety of dementia syndromes and mild cognitive impairment (MCI) within a memory clinic population. Methods: Of the 1,193 consecutive patients with cognitive impairment (CI) who received 1 11C-PIB PET or 18F-AV45 PET or both 11C-PIB PET and 18F-AV45 PET, 960 were diagnosed with AD, 36 with frontotemporal dementia (FTD), 5 with dementia with Lewy bodies, 144 with MCI, 29 with vascular dementia, 4 with corticobasal syndrome, and 15 with unclassifiable dementia. Baseline clinical diagnoses were independently established without access to PET imaging results. Apolipoprotein E (ApoE) genotype analysis was performed on CI patients and 231 sex- and age-matched controls. Results: Of the 1,193 CI patients, 860 (72.1%) were amyloid-positive. The prevalence of amyloid positivity in AD and MCI patients was 86.8% (833/960) and 9.7% (14/144), respectively. In FTD patients, the prevalence of β-amyloid deposits was 5.6% (2/36). In the 4 corticobasal syndrome patients, 2 were amyloid-positive. Three of the 5 patients with dementia with Lewy bodies showed amyloid positivity, as did 6 of the 29 vascular dementia (20.7%) patients. The ApoEε4 allele frequency was significantly increased in amyloid-positive CI patients (30.5%) as compared with other amyloid-negative CI patients (14%) or controls (7.3%). Conclusion: Amyloid imaging may potentially be the most helpful parameter for differential diagnosis in dementia, particularly to distinguish between AD and FTD. Amyloid PET can be used in conjunction with the ApoEε4 allele genetic risk test for amyloid deposits.

Application of 18F-AV45 PET imaging in subtle cognitive decline and mild cognitive impairment patients

Objective To investigate the correlations between cerebral β-amyloid (Aβ) deposition assessed by 18F-florbetapir (AV45) PET imaging and clinical cognitive symptoms in patients with subtle cognitive decline (SCD) and mild cognitive impairment (MCI). Methods Data of twenty-four patients (11 males, 13 females, age: (63.2±7.6) years) diagnosed as SCD (n=15) or MCI (n=9) from December 2018 to March 2019 in Shanghai Jiao Tong University Affiliated Sixth People′s Hospital were collected prospectively. All patients underwent 18F-AV45 PET imaging, brain MRI T1 scan and Mini-Mental State Examination (MMSE) within two weeks. 18F-AV45 PET images were analyzed visually (positive, mild positive, negative). After being pretreated according to the MRI, 18F-AV45 PET images were analyzed semi-quantitatively by calculating the standardized uptake value ratio (SUVR) of Aβ deposition in 8 regions of interest (ROIs; frontal lobe, lateral parietal lobe, lateral temporal lobe, medial temporal lobe, occipital lobe, basal ganglia, posterior cingulate and precuneus), with cerebellar gray matter as the reference. Partial correlation coefficients between regional SUVRs and MMSE score were calculated. Results 18F-AV45 PET imaging showed that 16 patients with positive results and 8 patients with mild positive results. MMSE score of 24 patients was 28.2±2.0, and the SUVR was 0.93-1.87. Correlation analysis revealed that Aβ deposition in frontal cortex (r=-0.432), posterior cingulate lobe (r=-0.434) and precuneus (r=-0.418) was negatively correlated with MMSE score (all P 0.05). Conclusion 18F-AV45 PET imaging can noninvasively detect brain Aβ deposition in patients, and can effectively reflect the clinical cognitive status of patients with SCD and MCI to a certain extent. Key words: Cognition disorders; Amyloid; Positron-emission tomography

Examining the Relationship between a Verbal Incidental Learning Measure from the WAIS-IV and Neuroimaging Biomarkers for Alzheimer’s Pathology

ABSTRACT Convergent validation of a verbal incidental learning (IL) task from the WAIS-IV using neuroimaging biomarkers is warranted to understand its sensitivity to Alzheimer’s disease (AD) pathology. Fifty-five memory clinic patients aged 59 to 87 years received neuropsychological assessment, and measures of IL and quantitative brain imaging. Worse IL-Total Score and IL-Similarities performances were significantly associated with smaller hemispheric hippocampal volumes. IL measures were not significantly correlated with cerebral β-amyloid burden, though a trend was present and effect sizes were mild. These hippocampal volume results suggest that this IL task may be sensitive to AD pathology along the AD continuum.

Dopaminergic Depletion, β-Amyloid Burden, and Cognition in Lewy Body Disease.

We aimed to determine the association between striatal dopaminergic depletion, cerebral β-amyloid deposition, and cognitive dysfunction in Lewy body disease (LBD). This cross-sectional study recruited 48 LBD patients (30 with dementia, 18 with mild cognitive impairment) and 15 control subjects from a university-based hospital. We measured the striatal dopamine transporter (DAT) activity and regional β-amyloid burden using N-(3-[18 F]fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) nortropane (FP-CIT) positron emission tomography (PET) and 18 F-florbetaben (FBB) PET, respectively. The relationship between striatal FP-CIT uptake, regional cortical FBB uptake, and cognitive function scores was evaluated using path analyses. We also investigated the effects of striatal FP-CIT uptake and cortical FBB uptake on the interval between motor symptom and dementia onset. Reduced striatal FP-CIT uptake was associated with increased FBB uptake in the posterior cortical regions, most prominently in the occipital cortices. Reduced FP-CIT uptake in the anterior putamen was associated with visuospatial dysfunction with mediation of increased occipital FBB uptake. Reduced FP-CIT uptake in the posterior putamen and an increased parietal FBB uptake were independently associated with memory dysfunction. Reduced striatal FP-CIT uptake was associated with attention, language, and frontal/executive dysfunction, independent of amyloid deposition. Increased FBB uptake, especially in the parietal cortex, was associated with earlier onset of dementia. Our results suggest that occipital β-amyloid deposition may contribute to the association between striatal dopaminergic depletion and visuospatial dysfunction in LBD patients. Although the effects of reduced DAT activity are more prominent than those of β-amyloid burden on cognitive dysfunction, the latter affects the onset of cognitive dysfunction. ANN NEUROL 2020;87:739-750.

Acetyl-11-keto-β-boswellic acid ameliorates cognitive deficits and reduces amyloid-β levels in APPswe/PS1dE9 mice through antioxidant and anti-inflammatory pathways

Alzheimer's disease (AD) is a complex disease involved oxidative stress and inflammation in its pathogenesis. Acetyl-11-keto-β-boswellic acid (AKBA) is an active triterpenoid compound from extracts of Boswellia serrata, which has been widely used as an antioxidant and anti-inflammatory agent. The present study was to determine whether AKBA, a novel candidate, could protect against cognitive and neuropathological impairments in AD. We found that AKBA treatment resulted in a significant improvement of learning and memory deficits, a dramatic decrease in cerebral amyloid-β (Aβ) levels and plaque burden, a profound alleviation in oxidative stress and inflammation, and a marked reduction in activated glial cells and synaptic defects in the APPswe/PS1dE9 mice. Furthermore, amyloid precursor protein (APP) processing was remarkably suppressed with AKBA treatment by inhibiting beta-site APP cleaving enzyme 1 (BACE1) protein expression to produce Aβ in the APPswe/PS1dE9 mice brains. Mechanistically, AKBA modulated antioxidant and anti-inflammatory pathways via increasing nuclear erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression, and via declining phosphorylation of inhibitor of nuclear factor-kappa B alpha (IκBα) and p65. Collectively, our findings provide evidence that AKBA protects neurons against oxidative stress and inflammation in AD, and this neuroprotective effect involves the Nrf2/HO-1 and nuclear factor-kappa B (NF-κB) signaling pathways.

Probing Estrogen Sulfotransferase-Mediated Inflammation with [11C]-PiB in the Living Human Brain.

2-(4'- [11C]Methylaminophenyl)-6-hydroxybenzothiazole ([11C]-PiB), purportedly a specific imaging agent for cerebral amyloid-β plaques, is a specific, high affinity substrate for estrogen sulfotransferase (SULT1E1), an enzyme that regulates estrogen homeostasis. In this work, we use positron emission tomography (PET) imaging with [11C]-PiB to assess the functional activity of SULT1E1 in the brain of moyamoya disease patients. Ten moyamoya subjects and five control patients were evaluated with [11C]-PiB PET and structural MRI scans. Additionally, a patient with relapsing-remitting multiple sclerosis (RRMS) received [11C]-PiB PET scans before and after steroidal and immunomodulatory therapy. Parametric PET images were established to assess SULT1E1 distribution in the inflamed brain tissue. Increased [11C]-PiB SRTM DVR in the thalamus, pons, corona radiata, and internal capsule of moyamoya cohort subjects was observed in comparison with controls (p ≤ 0.01). This was observed in patients without treatment, with collateralization, and also after radiation. The post-treatment [11C]-PiB PET scan in one RRMS patient also revealed substantially reduced subcortical brain inflammation. In validation studies, [11C]-PiB autoradiography signal in the peri-infarct area of the rat middle cerebral arterial occlusion stroke model was shown to correlate with SULT1E1 immunohistochemistry. Strong [11C]-PiB PET signal associated with intracranial inflammation in the moyamoya syndrome cohort and a single RRMS patient appears consistent with functional imaging of SULT1E1 activity in the human brain. This preliminary work offers substantial and direct evidence that significant [11C]-PiB PET focal signals can be obtained from the living human brain with intracranial inflammation, signals not attributable to amyloid-β plaques.

Long-term effects of intracranial islet grafting on cognitive functioning in a rat metabolic model of sporadic Alzheimer's disease-like dementia.

Accumulating evidence suggests that Alzheimer’s disease is associated with brain insulin resistance, as are some other types of dementia. Intranasal insulin administration has been suggested as a potential approach to overcoming brain insulin resistance and improving cognitive functions. Islet transplantation into the cranial subarachnoid cavity was used as an alternative route for insulin delivery into the brain. Recently, the authors showed the short-term beneficial cognitive effect of a small number of intracranially grafted islets in rats with cognitive dysfunction induced by intracerebroventricular administration of streptozotocin (icv-STZ). This was associated with continuous and safe insulin delivery to the rat brain. The current study investigated the long-term effect of intracranial grafting of islets on cognitive functioning in icv-STZ rats. Severe dementia, associated with obesity and cerebral amyloid-β angiopathy, was induced in Lewis inbred rats by icv-STZ. Two months after icv-STZ, one hundred syngeneic islets were transplanted into the cranial subarachnoid space. Two and six months later, cognitive alterations were assessed by Morris water-maze tests. Islet graft survival was evaluated by immunohistochemical and biochemical assays. Improvement was found in spatial learning and memory of grafted rats as opposed to the sham-operated icv-STZ rats. The grafted islets showed intact morphology, intensive expression of insulin, glucagon and glucose transporter 2. Normoglycemic obesity and cerebral amyloid-β angiopathy were found in both grafted and sham-operated icv-STZ rats. In conclusion, islet grafting into cranial subarachnoid space provides an efficient and safe approach for insulin delivery to the brain, leading to a long-term attenuation of icv-STZ-induced cognitive dysfunction.

The Challenge of Antidepressant Therapeutics in Alzheimer's Disease.

The link between depression and Alzheimer's disease (AD) is controversial, because it is not clear if depression is an independent risk factor for the disease or a prodromal symptom in the older population. Cerebral amyloid-β (Aβ) peptide deposition is associated with both cognitive symptoms and neuropsychiatric symptoms (NPS), which may be a biological mechanism of compensation. Despite the widespread use of antidepressant therapeutics (30-50% of patients with AD/dementia are on antidepressants), there is mixed evidence regarding the benefits from their use in AD depression. Monoaminergic antidepressant drugs have shown only modest or no clinical benefits. Therefore, it is important to understand the reason of this drug-resistance and the relationship between antidepressant drugs and the Aβ peptide. The goal of the present review is to highlight the etiology of depression in patients affected by AD in comparison to depressive disorders without AD, and to speculate on more appropriate and alternative therapeutics.

Major Surgery Affects Memory in Individuals with Cerebral Amyloid-β Pathology.

Major surgery has been associated with perioperative neurocognitive disorders (PND), but the contributing factors and long-term prognosis are uncertain. We hypothesize that preclinical Alzheimer's disease (AD) might predispose to cognitive deterioration after surgery. To analyze the effect of amyloid-β on the cognitive trajectory after orthopedic surgery in a sample of non-demented subjects. Non-demented individuals older than 65 years that were on the waiting list for orthopedic surgery with spinal anesthesia underwent a neuropsychological assessment before and after surgery. During surgery, cerebrospinal fluid samples were obtained to determine AD biomarkers. Cumulative incidence of PND was 55.2%during a mean follow-up of nine months. The most affected cognitive domains were executive function and constructional praxis. The presence of abnormal levels of amyloid-β was associated to a postoperative impairment in verbal and visual memory tests. According to their AD biomarker profile, participants were categorized as either Amyloid Positive (A+) or Amyloid Negative (A-). The incidence of PND did not differ between both groups. The A- group showed a tendency similar to the global sample, worsening in executive function tests and improving on memory scales due to practice effects. In contrast, the A + group showed a notable worsening on memory performance. Our findings support the hypothesis that surgery may promote or accelerate memory decline in cognitively asymptomatic subjects with brain amyloid-β deposits.

Population-based blood screening for preclinical Alzheimer's disease in a British birth cohort at age 70.

Alzheimer’s disease has a preclinical stage when cerebral amyloid-β deposition occurs before symptoms emerge, and when amyloid-β-targeted therapies may have maximum benefits. Existing amyloid-β status measurement techniques, including amyloid PET and CSF testing, are difficult to deploy at scale, so blood biomarkers are increasingly considered for screening. We compared three different blood-based techniques—liquid chromatography-mass spectrometry measures of plasma amyloid-β, and single molecule array (Simoa) measures of plasma amyloid-β and phospho-tau181—to detect cortical 18F-florbetapir amyloid PET positivity (defined as a standardized uptake value ratio of >0.61 between a predefined cortical region of interest and eroded subcortical white matter) in dementia-free members of Insight 46, a substudy of the population-based British 1946 birth cohort. We used logistic regression models with blood biomarkers as predictors of amyloid PET status, with or without age, sex and APOE ε4 carrier status as covariates. We generated receiver operating characteristics curves and quantified areas under the curves to compare the concordance of the different blood tests with amyloid PET. We determined blood test cut-off points using Youden’s index, then estimated numbers needed to screen to obtain 100 amyloid PET-positive individuals. Of the 502 individuals assessed, 441 dementia-free individuals with complete data were included; 82 (18.6%) were amyloid PET-positive. The area under the curve for amyloid PET status using a base model comprising age, sex and APOE ε4 carrier status was 0.695 (95% confidence interval: 0.628–0.762). The two best-performing Simoa plasma biomarkers were amyloid-β42/40 (0.620; 0.548–0.691) and phospho-tau181 (0.707; 0.646–0.768), but neither outperformed the base model. Mass spectrometry plasma measures performed significantly better than any other measure (amyloid-β1-42/1-40: 0.817; 0.770–0.864 and amyloid-β composite: 0.820; 0.775–0.866). At a cut-off point of 0.095, mass spectrometry measures of amyloid-β1-42/1-40 detected amyloid PET positivity with 86.6% sensitivity and 71.9% specificity. Without screening, to obtain 100 PET-positive individuals from a population with similar amyloid PET positivity prevalence to Insight 46, 543 PET scans would need to be performed. Screening using age, sex and APOE ε4 status would require 940 individuals, of whom 266 would proceed to scan. Using mass spectrometry amyloid-β1-42/1-40 alone would reduce these numbers to 623 individuals and 243 individuals, respectively. Across a theoretical range of amyloid PET positivity prevalence of 10–50%, mass spectrometry measures of amyloid-β1-42/1-40 would consistently reduce the numbers proceeding to scans, with greater cost savings demonstrated at lower prevalence.

Association of Intracranial Atherosclerotic Disease With Brain β-Amyloid Deposition

Intracranial atherosclerotic disease (ICAD) is an important cause of stroke and has also been recently identified as an important risk factor for all-cause dementia, but the mechanism of its association with cognitive performance is not fully understood. To test the hypothesis that ICAD is associated with cerebral β-amyloid deposition as a marker of Alzheimer disease. This cross-sectional analysis of data collected from August 2011 through November 2014 was a community-based cohort study conducted in 3 US communities. Of 346 adults without dementia aged 70 to 90 years who were sequentially recruited from 3 of 4 sites of the larger Atherosclerosis Risk in Communities study into a study of brain florbetapir positron emission tomography (ARIC-PET), 300 met inclusion criteria. A total of 589 were approached about recruitment, of whom 346 (58.7%) consented (the remainder either met exclusion criteria for ARIC-PET or refused to participate). Data were analyzed from July 2017 through October 2019. Intracranial atherosclerotic disease presence, frequency, and extent of stenosis, by high-resolution vessel wall magnetic resonance imaging. Global cortical standardized uptake value ratio (SUVR) of greater than 1.2 as measured by florbetapir PET. Models were conducted using logistic regression methods. In secondary analyses, we tested effect modifications by apolipoprotein E ε4 genotype with interaction terms and in stratified models and evaluated regional patterns of associations. In 300 participants (mean [SD] age, 76 [5] years; 132 African American individuals [44%], 167 women [56%], and 94 carriers of at least 1 apolipoprotein E ε4 allele [31%]), ICAD was found in 105 participants (35%) and mean (SD) SUVR was higher in individuals with vs without intracranial plaques (1.34 [0.29] vs 1.27 [0.23]; P = .03). In adjusted models, ICAD presence (plaque presence [adjusted odds ratio (aOR), 1.20; 95% CI, 0.69-2.07] and frequency [aOR, 1.10; 95% CI, 0.96-1.26]) was not associated significantly with elevated SUVR in the total sample. Furthermore, modest stenosis of the intracranial vessels (defined as >50% stenosis) was not associated with elevated SUVR (aOR, 2.33; 95% CI, 0.82-6.60). In this community-based cohort of adults without dementia, intracranial atherosclerotic plaque or stenosis was not associated with brain β-amyloid deposition.

Geniposidic acid ameliorates spatial learning and memory deficits and alleviates neuroinflammation via inhibiting HMGB-1 and downregulating TLR4/2 signaling pathway in APP/PS1 mice

Geniposidic acid (GPA) is an extract from Eucommia ulmoides Oliv. Bark (Eucommiaceae). Accumulating evidences have reported GPA has anti-aging, anti-oxidative stress, anti-inflammatory and neurotrophic effects on neurons. However, whether GPA could alleviate memory deficits in Alzheimer's disease animal models is not clear. We aimed to investigate the effect of GPA treatment on cognitive performance, Aβ deposition and glial cells activation in the transgenic mouse model of AD. 6–7 months APP/PS1 mice were given GPA for 90 days; behavioral experiments were executed to estimate the memory and spatial learning abilities of mice, and the mechanism of neuroprotective effect of GPA was investigated with a focus on amyloid-β deposition, astrocytes and microglia activation and neuroinflammation. GPA treatment significantly improved the spatial learning and memory abilities and also decreased cerebral amyloid-β deposition in APP/PS1 mice. Via HE staining, we found that GPA could ameliorate histopathological changes in cerebrum. We also found that GPA treatment inhibited the activation of astrocytes and microglia, down-regulated the expression of pro-inflammatory cytokines and iNOS, and up-regulated the expression of anti-inflammatory cytokines and Arg-1. In addition, GPA down-regulated the gene expression of HMGB-1 receptors (TLR2, TLR4 and RAGE) then mediated MyD88, TRAF6 and phospho-ERK1/2, subsequently modulated the expression of key AP-1 and NF-κB family members (c-Fos, c-Jun and p65). The reversal of the pro-inflammatory state suggested GPA can serves as a multi-target candidate by alleviating Aβ deposition and neuroinflammation for the auxiliary therapy of Alzheimer's disease.

Risk of developing cerebral β-amyloid plaques with posttranslational modification among HIV-infected adults.

Evidence of accelerated brain aging among HIV-infected adults argues for the increased risk of developing cerebral β-amyloid (Aβ) plaques. We compared the frequency of Aβ plaque-bearing cases in our HIV cohort with that in a general cohort reported by Braak et al. We explored posttranslationally modified Aβ forms (N3pE, E22P, phospho-Ser8) in plaques and E22P-Aβ in the postmortem cerebrospinal fluid (CSF) in the HIV cohort. Clinicopathological study of HIV-infected adults. To assess frontal Aβ plaque deposition, we conducted immunohistochemistry for generic Aβ (4G8) and three modified Aβ forms. We determined CSF E22P-Aβ levels by ELISA. We found 4G8-Aβ plaques in 29% of 279 HIV-infected cases. Within the age range of 31-70 years, the frequency of 4G8-Aβ plaque-bearing cases was higher in our HIV cohort (n = 273) compared with the general cohort (n = 1110) overall (29.3 vs. 25.8%) and across four age groups by decade (odds ratio 2.35, P < 0.0001). In HIV-infected cases with (n = 37) and without (n = 12) 4G8-Aβ plaques, modified Aβ forms occurred in order: N3pE, E22P, and phospho-Ser8. In CSF assays of HIV-infected cases with (n = 27; 17 focal, 10 widespread) and without (n = 11) 4G8-Aβ plaques, the median E22P-Aβ/Aβ40 ratio was higher among cases with widespread plaques than in cases with focal or absent plaques (P = 0.047). Our findings suggest HIV-infected adults are at increased risk of developing cerebral Aβ plaques. The occurrence of modified Aβ forms in order suggests the progression stages of Aβ plaque deposition. The potential for E22P-Aβ as a CSF biomarker of cerebral Aβ plaques should be investigated.

WBQ5187, a Multitarget Directed Agent, Ameliorates Cognitive Impairment in a Transgenic Mouse Model of Alzheimer's Disease and Modulates Cerebral β-Amyloid, Gliosis, cAMP Levels, and Neurodegeneration.

Previously, we designed, synthesized, and evaluated a series of quinolone-benzofuran derivatives as multitargeted anti-Alzheimer's disease (anti-AD) compounds, and we discovered that WBQ5187 possesses superior anti-AD bioactivity. In this work, we investigated the pharmacokinetics of this new molecule, as well as its therapeutic efficacy in restoring cognition and neuropathology, in the APP/PS1 mouse model of AD. Pharmacokinetic analyses demonstrated that WBQ5187 possessed rational oral bioavailability, metabolic stability, and excellent blood-brain barrier (BBB) permeability. Pharmacodynamics studies indicated that a 12-week treatment with the lead compound at doses of 40 mg/kg or higher significantly enhanced the learning and memory performance of the APP/PS1 transgenic mice, and the effect was more potent than that of clioquinol (CQ). Furthermore, WBQ5187 notably reduced cerebral β-amyloid pathology, gliosis, and neuronal cell loss and increased the levels of cAMP in the hippocampus of these mice. The surrogate measures of emesis indicated that WBQ5187 had no effect at its cognitive effective doses. Overall, our results demonstrated that this compound markedly improves cognitive and spatial memory functions in AD mice and represents a promising pharmaceutical agent with potential for the treatment of AD.

Hippocampal subfield volumes and pre-clinical Alzheimer's disease in 408 cognitively normal adults born in 1946.

The human hippocampus comprises a number of interconnected histologically and functionally distinct subfields, which may be differentially influenced by cerebral pathology. Automated techniques are now available that estimate hippocampal subfield volumes using in vivo structural MRI data. To date, research investigating the influence of cerebral β-amyloid deposition-one of the earliest hypothesised changes in the pathophysiological continuum of Alzheimer's disease-on hippocampal subfield volumes in cognitively normal older individuals, has been limited. Using cross-sectional data from 408 cognitively normal individuals born in mainland Britain (age range at time of assessment = 69.2-71.9 years) who underwent cognitive assessment, 18F-Florbetapir PET and structural MRI on the same 3 Tesla PET/MR unit (spatial resolution 1.1 x 1.1 x 1.1. mm), we investigated the influences of β-amyloid status, age at scan, and global white matter hyperintensity volume on: CA1, CA2/3, CA4, dentate gyrus, presubiculum and subiculum volumes, adjusting for sex and total intracranial volume. Compared to β-amyloid negative participants (n = 334), β-amyloid positive participants (n = 74) had lower volume of the presubiculum (3.4% smaller, p = 0.012). Despite an age range at scanning of just 2.7 years, older age at time of scanning was associated with lower CA1 (p = 0.007), CA4 (p = 0.004), dentate gyrus (p = 0.002), and subiculum (p = 0.035) volumes. There was no evidence that white matter hyperintensity volume was associated with any subfield volumes. These data provide evidence of differential associations in cognitively normal older adults between hippocampal subfield volumes and β-amyloid deposition and, increasing age at time of scan. The relatively selective effect of lower presubiculum volume in the β-amyloid positive group potentially suggest that the presubiculum may be an area of early and relatively specific volume loss in the pathophysiological continuum of Alzheimer's disease. Future work using higher resolution imaging will be key to exploring these findings further.