Brain Amyloid-β Deposition Research Articles

Association of cerebrospinal fluid α-synuclein with total and phospho-tau181 protein concentrations and brain amyloid load in cognitively normal subjective memory complainers stratified by Alzheimer's disease biomarkers

IntroductionSeveral neurodegenerative brain proteinopathies, including Alzheimer's disease (AD), are associated with cerebral deposition of insoluble aggregates of α-synuclein. Previous studies reported a trend toward increased cerebrospinal fluid (CSF) α-synuclein (α-syn) concentrations in AD compared with other neurodegenerative diseases and healthy controls. MethodsThe pathophysiological role of CSF α-syn in asymptomatic subjects at risk of AD has not been explored. We performed a large-scale cross-sectional observational monocentric study of preclinical individuals at risk for AD (INSIGHT-preAD). ResultsWe found a positive association between CSF α-syn concentrations and brain β-amyloid deposition measures as mean cortical standard uptake value ratios. We demonstrate positive correlations between CSF α-syn and both CSF t-tau and p-tau181 concentrations. DiscussionAnimal models presented evidence, indicating that α-syn may synergistically and directly induce fibrillization of both tau and β-amyloid. Our data indicate an association of CSF α-syn with AD-related pathophysiological mechanisms, during the preclinical phase of the disease.

Fluorescent Imaging of Amyloid-β Deposits in Brain: An Overview of Probe Development and a Highlight of the Applications for In Vivo Imaging.

The β-amyloid (Aβ) plaques presented within the brain parenchyma have been widely proved to be one of the hallmarks of Alzheimer's disease (AD). According to the amyloid cascade hypothesis, the accumulation of Aβ plaques in the brain is intrinsic and fundamental for disease onset, and much research about the early diagnosis of AD is based on this. A recent development in Aβ detection has focused on the mapping of the molecule events in the brain using an exquisite, noninvasive, and inexpensive optical imaging technique, which has stimulated the rapid development of Aβ-specific fluorescent probes. Among them, nearinfrared (NIR) fluorophores have gained adequate attention due to the weak light attenuation in tissues and avoidance from auto-fluorescence of biological matter. In this review, we showcase the current developments of fluorescent probes that are subject to in vitro or in vivo detection of Aβ plaques in the brain, and give an emphasis on the probes used for in vivo twophoton microscopy and NIR imaging by highlighting their biological and photochemical properties.

Effects of Lignans from Schisandra chinensis Rattan Stems against Aβ1-42-Induced Memory Impairment in Rats and Neurotoxicity in Primary Neuronal Cells.

Oxidative stress, which is caused by Amyloid-β deposition in brain, plays an important role in Alzheimer’s disease. In this study, we found that lignans from Schisandra chinensis rattan stems (rsSCH-L) could reduce the escape latency and the distance travelled by the Aβ1–42 injected rats while the crossing platform time was enhanced in the Morris water maze test. Further research demonstrated that lignans from rsSCH-L attenuated Aβ1-42-induced neuronal cell injury by increasing the content of SOD and GSH-Px and decreasing the levels of LDH, ROS, and MDA. Moreover, rsSCH-L also inhibited the apoptosis of primary neuronal cells. The mechanisms of the apoptosis were related with the downregulation of caspase-3, caspase-8, Bax, and upregulation of Bcl-2. Taken together, the results show that rsSCH-L can improve cognitive ability in vivo. Meanwhile rsSCH-L exhibit a neuroprotective environment against oxidative stress and apoptosis in vitro. Therefore, rsSCH-L may be a potential therapeutic agent for this neurodegenerative disease.

Pulse pressure is associated with plasma amyloid-β transport dysfunction.

Increased pulse pressure (PP) has been implicated in the development and progression of Alzheimer's disease in middle-aged and elderly adults. Considering the close relationship between peripheral amyloid-β clearance and brain amyloid-β deposition, we investigated the potential association between PP and plasma amyloid-β transport function. In this cross-sectional study, a total of 1118 participants underwent a health assessment and quantification of plasma amyloid-β and amyloid-β transporter expression. Relationships between plasma levels of amyloid-β1-40, amyloid-β1-42, soluble low-density lipoprotein receptor-related protein-1 (sLRP1), soluble receptor for advanced glycation end products (sRAGE), and PP were determined using multiple linear regressions. PP was a significant determinant of amyloid-β1-40 level (β = 0.059, P = 0.036) and log-transformed sRAGE (β = -0.002, P = 0.029) independent of age, sex, body mass index, pulse rate, mean arterial pressure, blood glucose, blood lipids, lifestyle, and medical history. Additionally, log-transformed soluble low-density lipoprotein receptor-related protein-1 and log-transformed sRAGE were positively associated with plasma amyloid-β1-40 level (β = 3.610, P < 0.001; β = 2.573, P = 0.001). Similar associations were observed between log-transformed sRAGE and plasma amyloid-β1-42 level (β = 1.350, P = 0.022). An elevation in PP is associated with increased plasma amyloid-β1-40 and decreased log-transformed sRAGE among individuals not taking antihypertensive medication. The underlying mechanism of this effect may be relevant to peripheral amyloid-β clearance.

Predicting brain amyloid-β deposition using easy Z-score analysis

Predicting brain amyloid-β deposition using easy Z-score analysis

Abstract P448: Interaction Between Ischemic Brain Injury and Amyloid-β Deposition in Cognitive Decline; Possible Cognitive Protection by AT 2 Receptor Activation

Objectives: Cerebrovascular damage could breakdown amyloid-β (Aβ) clearance and accelerate Aβ deposition. We examined the interaction between ischemic brain damage and Aβ deposition in cognitive function, focusing on the roles of angiotensin II type 2 (AT 2 ) receptor in vascular smooth muscle cells (VSMC). Methods: Male wild-type mice (WT) or the mice with VSMC-specific AT 2 receptor overexpression (smAT 2 ) were used. Mice were subjected to ICV injection of Aβ1-40. Ischemic brain injury was induced by bilateral common carotid artery occlusion (BCCAO) 24 hours after Aβ1-40 injection. Three weeks after Aβ1-40 injection, cognitive function was evaluated by the Morris water maze test. Brain samples obtained 8 days after Aβ1-40 injection were used to study the related signals. Results: ICV injection of Aβ1-40 in WT showed impaired cognitive function (arriving time to platform at day 5: control, 26.53±4.46 sec; Aβ, 65.35±7.44 sec), whereas BCCAO alone did not decline significantly cognitive function. In contrast, BCCAO following Aβ1-40 injection exhibited more marked cognitive impairment (84.27±8.00 sec) compared to Aβ injection alone with the increase in expressions of NADPH oxidase subunits such as p22phox and p67phox in the hippocampus of mice. Aβ1-40 injection with BCCAO tended to increase the mRNA levels of inflammatory cytokines such as MCP-1 and TNFα. BCCAO significantly enhanced the expression of Aβ clearance factor, RAGE (receptor for advanced glycation end product). Aβ1-40 injection did not increase the neuron pyknosis in the hippocampus, whereas the number of neuron pyknosis was increased significantly with BCCAO (control, 6.33±0.88/field; Aβ with BCCAO, 46.33±4.10/field). On the other hand, smAT 2 did not show cognitive impairment, the changes of the expression for NADPH oxidase subunits and inflammatory cytokines, and neuron pyknosis, which were induced by BCCAO with/without Aβ1-40 injection in WT. Conclusion: Ischemic brain injury could enhance Aβ-induced cognitive impairment with possible involvement of enhanced oxidative stress, neuron degeneration, and breakdown of RAGE-mediated Aβ clearance. AT 2 receptor activation in VSMC could play inhibitory roles in the cognitive decline induced by ischemic brain damage and Aβ deposition.

Inhibitory Effect of Lycopene on Amyloid-β-Induced Apoptosis in Neuronal Cells

Alzheimer′s disease (AD) is a fatal neurodegenerative disease. Brain amyloid-β deposition is a crucial feature of AD, causing neuronal cell death by inducing oxidative damage. Reactive oxygen species (ROS) activate NF-κB, which induces expression of Nucling. Nucling is a pro-apoptotic factor recruiting the apoptosome complex. Lycopene is an antioxidant protecting from oxidative stress-induced cell damage. We investigated whether lycopene inhibits amyloid-β-stimulated apoptosis through reducing ROS and inhibiting mitochondrial dysfunction and NF-κB-mediated Nucling expression in neuronal SH-SY5Y cells. We prepared cells transfected with siRNA for Nucling or nontargeting control siRNA to determine the role of Nucling in amyloid-β-induced apoptosis. The amyloid-β increased intracellular and mitochondrial ROS levels, apoptotic indices (p53, Bax/Bcl-2 ratio, caspase-3 cleavage), NF-kB activation and Nucling expression, while cell viability, mitochondrial membrane potential, and oxygen consumption rate decreased in SH-SY5Y cells. Lycopene inhibited these amyloid-β-induced alterations. However, amyloid-β did not induce apoptosis, determined by cell viability and apoptotic indices (p53, Bax/Bcl-2 ratio, caspase-3 cleavage), in the cells transfected with siRNA for Nucling. Lycopene inhibited apoptosis by reducing ROS, and by inhibiting mitochondrial dysfunction and NF-κB-target gene Nucling expression in neuronal cells. Lycopene may be beneficial for preventing oxidative stress-mediated neuronal death in patients with neurodegeneration.

ProBDNF Accelerates Brain Amyloid-β Deposition and Learning and Memory Impairment in APPswePS1dE9 Transgenic Mice.

Alzheimer's disease (AD) is pathologically known for the amyloid-β (Aβ) deposition, neurofibrillary tangles, and neuronal loss in the brain. The precursor of brain-derived neurotrophic factor (proBDNF) before proteolysis has opposing functions to its mature form in neuronal survival and neurite growth. However, the role of proBDNF in the pathogenesis of AD remains unclear. To investigate the effects of proBDNF on neurons in vitro, and on learning and memory impairment and brain Aβ production in a transgenic AD mouse model (APPswePS1dE9). We here examined the effects of proBDNF on the viability (MTT assay) and neurite growth (morphologic measurement) of the primary neurons in vitro. After the intracerebroventricular injection of adeno-associated virus-proBDNF (AAV-proBDNF), we then investigated the learning and memory impairment (Morris water maze) and Aβ deposition in the brains of the AD mice. The results showed that proBDNF could inhibit neuronal viability and neurite growth in vitro, enhance Aβ levels, and accelerate its deposition in the brain, which was consistent with the learning and memory impairment of AD mice, likely dependent on the membrane receptor of p75NTR. Our findings suggest that proBDNF may exert a crucially negative effect during AD pathogenesis andprogression.

The evaluation of brain perfusion SPECT using an easy Z-score imaging system in the mild cognitive impairment subjects with brain amyloid-β deposition

ObjectiveThe analysis of 99mTc-ECD single-photon emission computed tomography (SPECT) images using the easy Z-score imaging system (eZIS) program is useful for the diagnosis of early AD in daily medical practice. However, it remains unclear whether eZIS analysis can identify the amnestic mild cognitive impairment (MCI) subjects with brain amyloid-β deposition. The aim of this study was to evaluate the usefulness of an eZIS analysis for predicting amnestic MCI subjects with brain amyloid β deposition. Patients and methodsTwenty-three subjects with MCI (10 men and 13 women, mean age; 74.2 years) underwent brain perfusion SPECT and 11C-Pittsburgh Compound B positron emission tomography (PiB-PET). MCI subjects were divided into PiB-positive and PiB-negative subgroups. SPECT data was analyzed using the Specific Volume of interest Analysis of the eZIS program. Three indicators (severity, extent, and ratio) were calculated automatically and compared between the two subgroups. ResultsFive of 12 (41.7%) subjects in the PiB-positive subgroup and three of 11 (27.3%) subjects in the PiB-negative subgroup showed the abnormal value for each indicator. The frequency of subjects with abnormal ratio values was significantly higher in the PiB-positive subgroup compared to the PiB-negative subgroup (p=0.02), whereas that of subjects with abnormal values in severity and extent did not differ among the two subgroups. In particular, all subjects in the PiB-negative subgroup showed normal ratio values. Moreover, the subjects with abnormal values on two indicators, including ratio, or on all three indicators, showed PiB-positive. ConclusionThe analysis of brain perfusion SPECT using an eZIS program cannot identify the amnestic MCI subjects with brain amyloid-β deposition. However, abnormal three indicators or normal ratio values may be helpful SPECT findings for predicting the results of PiB-PET in the amnestic MCI subjects.

Amyloid-β Deposition and Long-Term Progression in Mild Cognitive Impairment due to Alzheimer's Disease Defined with Amyloid PET Imaging.

The aim was to evaluate brain amyloid-β (Aβ) deposition in patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) using amyloid PET imaging and clarify the relationship between the annual change in Aβ deposition and disease progression. Forty-eight MCI patients underwent neuropsychological assessment and amyloid PET imaging using [11C]-PIB over a follow-up of 5.7±1.5 years. Thirty-nine MCI patients who had an amyloid-positive scan were defined as MCI due to AD, and 9 MCI patients who had an amyloid-negative scan were included. Regions of interest were defined on co-registered MRI, and the PIB standardized uptake value ratio (SUVR) on the same regions was used over follow-up. Annual change in PIB SUVR was calculated. Patients with MCI due to AD had higher baseline PIB SUVR (1.81±0.32, n = 39, p < 0.01) and a greater annual rate of change in PIB SUVR (0.044±0.027, n = 39, p < 0.01) compared to amyloid-negative MCI patients. Twenty-eight (71.8%) progressed to AD. In patients who progressed during a short duration of 1.7±0.8 years, the annual rate of increase in PIB SUVR was 0.101±0.094 (n = 16, p < 0.05), which was greater compared to patients with long conversion or stable patients. There was a negative correlation between the annual rate of increase in PIB SUVR and duration of progression to AD among individual MCI converters (r = -0.47, n = 28, p < 0.05). The patients defined as MCI due to AD could progress to AD with a shorter period if they have a greater increased annual rate in brain Aβ deposition.

Abstract WP289: Interaction Between Stroke and Amyloid-β Deposition in Cognitive Function ~Possible Involvement of Antagonist Effect of AT 2 Receptor Activation~

Background and Aim: Stroke is known to be causally related with Alzheimer’s disease pathology and amyloid-β (Aβ) deposition has been suggested to induce cerebral amyloid angiopathy resulting in stroke-associated cognitive decline. Angiotensin (Ang) type 1 (AT 1 ) receptor activation impairs cognitive performance, whereas Ang II type 2 (AT 2 ) receptor stimulation has been reported to improve cognitive impairment. We examined the interaction between stroke and Aβ deposition in cognitive function, and the possible antagonist effect of AT 2 receptor in vascular smooth muscle cells (VSMC) on this cognitive decline. Methods: Adult (10-12 weeks old) male wild-type (WT) mice (C57BL/6J mice) or the mice with AT 2 receptor overexpression in VSMC (SMAT2) were used. Mice were subjected to intracerebroventricular (ICV) injection of Aβ1-40 following 15 minutes global brain ischemia operation. Three weeks after Aβ1-40 ICV injection, cognitive function of spatial learning memory was evaluated by the Morris water maze test. Brain samples were obtained after behavioral testing, and the expression of inflammatory cytokines and NADPH oxidase subunits were measured by real-time quantitative RT-PCR. Results: ICV injection of Aβ1-40 in WT mice showed impaired cognitive function. On the other hand, WT mice with transient global brain ischemia did not decline significantly cognitive function. In contrast, WT mice with Aβ1-40 ICV injection with global brain ischemia exhibited more marked cognitive impairment compared with control mice. These results suggested that transient brain ischemia and amyloid-β deposition exerted at least additive effects on cognitive impairment. This cognitive decline was accompanied with increased expressions of inflammatory cytokines such as monocyte chemoattractant protein-1 and NADPH oxidase subunits including p22 phox . On the other hand, SMAT 2 mice did not show cognitive impairment by global brain ischemia with/without Aβ1-40 ICV injection. Conclusion: Brain ischemia and amyloid-β deposition induced additive or synergistic effect on cognitive impairment. AT 2 receptor activation in VSMC could play an inhibitory role in the cognitive decline induced by brain ischemia and amyloid-β deposition.

Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis.

Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions.

ABCA1 deficiency and cellular cholesterol accumulation increases islet amyloidogenesis in mice.

Islet amyloid, a pathological feature of type 2 diabetes, forms from the aggregation of islet amyloid polypeptide (IAPP), a beta cell peptide that is produced and co-secreted with insulin. Cholesterol regulates amyloid-β processing, deposition and clearance, promoting amyloidogenesis in the brain. ATP-binding cassette transporter 1 (ABCA1) is a cholesterol efflux transporter that when absent increases and when overexpressed reduces brain amyloid-β deposition in mouse models of Alzheimer's disease. We examined whether alterations in ABCA1 expression and islet cholesterol content could also modulate islet amyloidogenesis. Thioflavin S staining for amyloid was performed in islets isolated from mice with beta cell expression of human IAPP (hIAPP (Tg/o)) and cultured for 8days following cholesterol loading, microRNA-33 overexpression (to reduce ABCA1 expression) or palmitate treatment in the presence or absence of ABCA1 overexpression or mevastatin treatment (to reduce cholesterol synthesis). hIAPP (Tg/o) mice were crossed with beta cell-specific Abca1-knockout mice (hIAPP (Tg/o) Abca1 (βKO)) and glucose tolerance and amyloid formation were assessed. Cholesterol loading and microRNA-33-induced reduction in islet ABCA1 expression increased Thioflavin S-positive amyloid in hIAPP (Tg/o) islets. Palmitate treatment also increased amyloid formation and this was reduced by both ABCA1 overexpression and mevastatin treatment. hIAPP (Tg/o) Abca1 (βKO) mice had increased islet cholesterol, accompanied by fasting hyperglycaemia, glucose intolerance, impaired in vivo insulin secretion and an increased islet proinsulin:insulin ratio. Amyloid area was increased in cultured hIAPP (Tg/o) Abca1 (βKO) islets compared with hIAPP (Tg/o) controls. These data suggest that elevations in islet cholesterol may lead to increases in IAPP aggregation and islet amyloid formation, further worsening beta cell function and glucose homeostasis.

An Eighteen-Month Helicobacter Infection Does Not Induce Amyloid Plaques or Neuroinflammation in Brains of Wild Type C57BL/6J Mice.

There is increasing evidence to support the role of infectious agents in the progression of Alzheimer's disease (AD), especially Helicobacter pylori (H. pylori). The impact of Helicobacter infection on the brain of non-AD predisposed mice was studied. For that, C57BL/6J mice were infected by oral gavage with H. pylori SS1 (n = 6) and Helicobacter felis (H. felis) (n=6) or not infected (n = 6) for evaluation of neuroinflammation (anti-GFAP and anti-iba1 immunohistochemistry) and amyloid-β deposition (thioflavin-S stain and anti-Aβ immunohistochemistry). After 18-month of infection, H. pylori SS1 and H. felis infection induced a strong gastric inflammation compared to non-infected mice, but did not induce brain neuroinflammation or amyloid-β deposition.

Review of 'the potential role of arterial stiffness in the pathogenesis of Alzheimer's disease'.

Arterial stiffness is emerging as an important risk marker for poor brain aging and dementia through its associations with cerebral small vessel disease, stroke, β-amyloid deposition, brain atrophy and cognitive impairment. Arterial stiffness directly relates the detrimental effects of hypertension on peripheral organs with dire consequences for the extensive microvasculature structure of the kidneys and brain. In this review, we discuss the evidence linking arterial stiffness, hypertension and brain structural abnormalities in older adults. In particular, we discuss the potential mechanisms linking arterial stiffness to brain β-amyloid deposition and dementia and potential therapeutic strategies to prevent hypertension's adverse effects on the brain.

Subjective Cognitive Complaints, Personality and Brain Amyloid-beta inCognitively Normal Older Adults.

Subjective cognitive complaints in otherwise normal aging are common but may be associated with preclinical Alzheimer disease in some individuals. Little is known about who is mostly likely to show associations between cognitive complaints and preclinical Alzheimer pathology. We sought to demonstrate associations between subjective complaints and brain amyloid-β in cognitively normal older adults; and to explore personality factors as potential moderators of this association. Cross-sectional observational study. Clinical neuroimaging research center. Community volunteer sample of 92 healthy older adults, screened for normal cognition with comprehensive neuropsychological evaluation. Subjective cognitive self-report measures included the Memory Functioning Questionnaire (MFQ), Cognitive Failures Questionnaire, and the Subjective Cognitive Complaint Scale. Personality was measured with the NEO Five Factor Inventory. Brain amyloid-β deposition was assessed with Pittsburgh compound B (PiB)-PET imaging. One of three cognitive complaint measures, the MFQ, was associated with global PiB retention (standardized beta=-0.230, p= 0.046, adjusting for age, sex and depressive symptoms). Neuroticism moderated this association such that only high neuroticism individuals showed the predicted pattern of high complaint-high amyloid-β association. Evidence for association between subjective cognition and brain amyloid-β deposition in healthy older adults is demonstrable but measure-specific. Neuroticism may moderate the MFQ-amyloid-β association such that it is observed in the context of higher trait neuroticism. Subjective cognitive complaints and neuroticism may reflect a common susceptibility toward psychological distress and negative affect, which are in turn risk factors for cognitive decline in aging and incident Alzheimer disease.

Overexpression of Heparanase Lowers the Amyloid Burden in Amyloid-β Precursor Protein Transgenic Mice

Heparan sulfate (HS) and HS proteoglycans (HSPGs) colocalize with amyloid-β (Aβ) deposits in Alzheimer disease brain and in Aβ precursor protein (AβPP) transgenic mouse models. Heparanase is an endoglycosidase that specifically degrades the unbranched glycosaminoglycan side chains of HSPGs. The aim of this study was to test the hypothesis that HS and HSPGs are active participators of Aβ pathogenesis in vivo. We therefore generated a double-transgenic mouse model overexpressing both human heparanase and human AβPP harboring the Swedish mutation (tgHpa*Swe). Overexpression of heparanase did not affect AβPP processing because the steady-state levels of Aβ1-40, Aβ1-42, and soluble AβPP β were the same in 2- to 3-month-old double-transgenic tgHpa*Swe and single-transgenic tgSwe mice. In contrast, the Congo red-positive amyloid burden was significantly lower in 15-month-old tgHpa*Swe brain than in tgSwe brain. Likewise, the Aβ burden, measured by Aβx-40 and Aβx-42 immunohistochemistry, was reduced significantly in tgHpa*Swe brain. The intensity of HS-stained plaques correlated with the Aβx-42 burden and was reduced in tgHpa*Swe mice. Moreover, the HS-like molecule heparin facilitated Aβ1-42-aggregation in an in vitro Thioflavin T assay. The findings suggest that HSPGs contribute to amyloid deposition in tgSwe mice by increasing Aβ fibril formation because heparanase-induced fragmentation of HS led to a reduced amyloid burden. Therefore, drugs interfering with Aβ-HSPG interactions might be a potential strategy for Alzheimer disease treatment.

Modulation of AD neuropathology and memory impairments by the isoprostane F2α is mediated by the thromboxane receptor

Beside amyloid-β plaques and neurofibrillary tangles, brain oxidative damage has been constantly implicated in Alzheimer's disease (AD) pathogenesis. Numerous studies demonstrated that F2-isoprostanes, markers of in vivo lipid peroxidation, are elevated in AD patients and mouse models of the disease. Previously, we showed that the 8-isoprostaneF2α, (8ISO) increases brain amyloid-β levels and deposition in the Tg2576 mice. However, no data are available on its effects on behavior and tau metabolism. To this end, we characterize the behavioral, biochemical, and neuropathologic effects of 8ISO in the triple transgenic mouse model. Compared with controls, mice receiving 8ISO showed significant memory deficits, increase in tau phosphorylation, activation of the cyclin kinase 5 pathway, and neuroinflammation. All these effects were blocked by pharmacologic blockade of the thromboxane receptor. Our findings establish the novel functional role that oxidative stress via the formation of this isoprostane plays in the development of cognitive impairments and AD-related tau neuropathology. It provides important preclinical support to the neurobiological importance of the thromboxane receptor as an active player in the pathogenesis of AD.

Neural compensation in older people with brain amyloid-β deposition.

The recruitment of additional neural resources may allow elderly adults to maintain normal cognition despite β-amyloid (Aβ) plaques. Previous fMRI studies have reported such hyperactivation, but it is currently unclear if these increases represent compensation or aberrant over-excitation. We found that older adults with Aβ deposition had reduced deactivations in task negative regions, but increased activation in task positive regions related to more detailed memory encoding. The association between higher activity levels and more detailed memories suggests that Aβ-related hyperactivation is a compensatory mechanism, potentially reflecting brain plasticity in response to Aβ deposition.

Plasma biosignature and brain pathology related to persistent cognitive impairment in late-life depression.

Cognitive impairment is highly prevalent among individuals with late-life depression (LLD) and tends to persist even after successful treatment. The biological mechanisms underlying cognitive impairment in LLD are complex and likely involve abnormalities in multiple pathways, or “cascades,” reflected in specific biomarkers. Our aim was to evaluate peripheral (blood-based) evidence for biological pathways associated with cognitive impairment in older adults with LLD. To this end, we used a data-driven comprehensive proteomic analysis (multiplex immunoassay including 242 proteins), along with measures of structural brain abnormalities (gray matter atrophy and white matter hyperintensity volume via MRI), and brain amyloid-β (Aβ) deposition (PiB-PET). We analyzed data from 80 older adults with remitted major depression (36 with Mild Cognitive Impairment (LLD+MCI) and 44 with normal cognitive function (LLD+NC)). LLD+MCI was associated with differential expression of 24 proteins (p <0.05 and q-value <0.30) related mainly to the regulation of immune-inflammatory activity, intracellular signaling, cell survival, and protein and lipid homeostasis. Individuals with LLD+MCI also showed greater white matter hyperintensity burden compared with LLD+NC (p=0.015). We observed no differences in gray matter volume or brain Aβ deposition between groups. Machine learning analysis showed that a group of three proteins (Apo AI, IL-12, and stem cell factor) yielded accuracy of 81.3%, sensitivity of 75%, and specificity of 86.4% in discriminating participants with MCI from those with normal cognitive function (with an averaged cross-validation accuracy of 76.3%, sensitivity of 69.4% and specificity of 81.8% with nested cross-validation considering the model selection bias). Cognitive impairment in LLD seems to be related to greater cerebrovascular disease along with abnormalities in immune-inflammatory control, cell survival, intracellular signaling, protein and lipid homeostasis, and clotting processes. These results suggest that individuals with LLD and cognitive impairment may be more vulnerable to accelerated brain aging and shed light on possible mediators of their elevated risk for progression to dementia.