Markers Of Alzheimer's Disease Pathology Research Articles

Increased Amyloid Precursor Protein and Tau Expression Manifests as Key Secondary Cell Death in Chronic Traumatic Brain Injury

In testing the hypothesis of Alzheimer's disease (AD)‐like pathology in late stage traumatic brain injury (TBI), we evaluated AD pathological markers in late stage TBI model. Sprague–Dawley male rats were subjected to moderate controlled cortical impact (CCI) injury, and 6 months later euthanized and brain tissues harvested. Results from H&E staining revealed significant 33% and 10% reduction in the ipsilateral and contralateral hippocampal CA3 interneurons, increased MHCII‐activated inflammatory cells in many gray matter (8–20‐fold increase) and white matter (6–30‐fold increased) regions of both the ipsilateral and contralateral hemispheres, decreased cell cycle regulating protein marker by 1.6‐ and 1‐fold in the SVZ and a 2.3‐ and 1.5‐fold reductions in the ipsilateral and contralateral dentate gyrus, diminution of immature neuronal marker by two‐ and onefold in both the ipsilateral and contralateral SVZ and dentate gyrus, and amplified amyloid precursor protein (APP) distribution volumes in white matter including corpus callosum, fornix, and internal capsule (4–38‐fold increase), as well as in the cortical gray matter, such as the striatum hilus, SVZ, and dentate gyrus (6–40‐fold increase) in TBI animals compared to controls (P's < 0.001). Surrogate AD‐like phenotypic markers revealed a significant accumulation of phosphorylated tau (AT8) and oligomeric tau (T22) within the neuronal cell bodies in ipsilateral and contralateral cortex, and dentate gyrus relative to sham control, further supporting the rampant neurodegenerative pathology in TBI secondary cell death. These findings indicate that AD‐like pathological features may prove to be valuable markers and therapeutic targets for late stage TBI. J. Cell. Physiol. 232: 665–677, 2017. © 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.

NIA-AA staging of preclinical Alzheimer disease: discordance and concordance of CSF and imaging biomarkers

The National Institute of Aging and Alzheimer's Association (NIA-AA) criteria for Alzheimer disease (AD) treat neuroimaging and cerebrospinal fluid (CSF) markers of AD pathology as if they would be interchangeable. We tested this assumption in 212 cognitively normal participants who have both neuroimaging and CSF measures of β-amyloid (CSF Aβ1-42 and positron emission tomography imaging with Pittsburgh Compound B) and neuronal injury (CSF t-tau and p-tau and structural magnetic resonance imaging) with longitudinal clinical follow-up. Participants were classified in preclinical AD stage 1 (β-amyloidosis) or preclinical AD stage 2+ (β-amyloidosis and neuronal injury) using the NIA-AA criteria, or in the normal or suspected non-Alzheimer disease pathophysiology group (neuronal injury without β-amyloidosis). At baseline, 21% of participants had preclinical AD based on CSF and 28% based on neuroimaging. Between modalities, staging was concordant in only 47% of participants. Disagreement resulted from low concordance between biomarkers of neuronal injury. Still, individuals in stage 2+ using either criterion had an increased risk for clinical decline. This highlights the heterogeneity of the definition of neuronal injury and has important implications for clinical trials using biomarkers for enrollment or as surrogate end point measures.

Premorbid personality characteristics and CSF markers of Alzheimer's pathology

Background Beginning as early as in young adulthood, personality characteristics may contribute to cognitive reserve by their influence on lifestyle and health-related behavior. A resilient personality profile may be associated with less cognitive and functional impairment in persons with cerebral Alzheimer's disease (AD) pathology. Aim The aim of this study was to investigate whether premorbid personality characteristics modulate the relationships between cognitive performance and AD pathology as measured using CSF biomarkers at preclinical and early clinical disease stages. Subjects and methods Sixty-eight patients with mild cognitive impairment or mild dementia and forty-two older subjects with normal cognition have been included. Premorbid personality characteristics were assessed by the NEO Personality Inventory Revised (as reported by a close relative) along with cognitive performance, functional status and CSF concentrations of Aβ1-42, tau, and ptau181. Multivariate regression analysis, including age, gender, education years, and APOEe4 genotype was used to evaluate associations between disease severity and premorbid personality scores, and the CSF markers of AD pathology. Results Overall, there were significant associations between Clinical dementia rating-Sum of boxes (CDRSOB) and the interactions of each personality trait with the ptau181/Aβ1-42 ratio. In subjects with cognitive impairment, there were significant associations between CDRSOB and the interactions of ptau181/Aβ1-42 ratio with Neuroticism, Extraversion, Openness and Conscientiousness. Significant results were also found using the interaction between different personality traits and the tau/Aβ1-42 to predict the CDRSOB. Discussion The findings suggest that premorbid personality characteristics modify the relationship between cerebral pathology and cognitive performance at very early clinical stages of AD.

Effects of rs3846662 Variants on HMGCR mRNA and Protein Levels and on Markers of Alzheimer's Disease Pathology.

3-Hydroxy-3-methyglutaryl coenzyme A reductase (HMGCR) is a cholesterol-regulating gene with statin relevance. rs3846662 being involved in regulation of HMGCR alternative splicing, we explored its impact on HMGCR messenger RNA (mRNA) and protein levels in the brain and the associations between those levels and levels of Alzheimer's disease pathological markers. We used brain samples derived from a cohort of 33 non-demented controls and 90 Alzheimer's disease autopsied-confirmed cases. HMGCR mRNA levels were determined in the frontal cortex (n = 114) and cerebellum (n = 110) using Taqman-qPCR, and HMGCR protein levels were determined in the frontal cortex (n = 117) using a commercial enzyme immunoassay. While densities of neurofibrillary tangles and senile plaques were determined in the frontal cortex (n = 74), total tau, phosphorylated Tau, and beta-amyloid 1-42 levels were determined in the frontal cortex (n = 94) and cerebellum (n = 91) using commercial enzyme immunoassays. Despite an increase in full-length HMGCR mRNA ratio in the frontal cortex of women carrying the AA genotype, there were no associations between rs3846662 and HMGCR mRNA or protein levels. An increased Δ13 HMGCR mRNA ratio was associated with increased levels of HMGCR proteins and neurofibrillary tangles in the frontal cortex but with reduced beta-amyloid 1-42 levels in the cerebellum, suggesting a brain cell type- or a disease progression-dependent association.

Dipping to clear amyloid

In this issue of Neurology ®, Tarumi et al.1 report an interesting study on a small sample of 40 persons with amnestic mild cognitive impairment (MCI) who were free of major vascular disease, sleep disorders, uncontrolled hypertension, and diabetes. They found that 2 indicators of a healthy, reactive vasculature, a greater reduction in systolic blood pressure (BP) when asleep (compared to the BP when awake), and greater cerebrovascular reactivity in response to physical activity, assessed using transcranial Doppler insonation of the intracranial middle cerebral artery, were each associated with lower PET amyloid burden in the posterior cingulate gyrus, a finding believed to be an early marker of Alzheimer disease pathology. Dr. Seshadri is funded by grants from the National Institute on Aging (RO1 AG033193, AG008122, AG049607, and U01 AG049505).

Neuropsychological Testing Predicts Cerebrospinal Fluid Amyloid-β in Mild Cognitive Impairment.

Psychometric tests predict conversion of mild cognitive impairment (MCI) to probable Alzheimer's disease (AD). Because the definition of clinical AD relies on those same psychometric tests, the ability of these tests to identify underlying AD pathology remains unclear. To determine the degree to which psychometric testing predicts molecular evidence of AD amyloid pathology, as indicated by cerebrospinal fluid (CSF) amyloid-β (Aβ)1-42, in patients with MCI, as compared to neuroimaging biomarkers. We identified 408 MCI subjects with CSF Aβ levels, psychometric test data, FDG-PET scans, and acceptable volumetric MR scans from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We used psychometric tests and imaging biomarkers in univariate and multivariate models to predict Aβ status. The 30-min delayed recall score of the Rey Auditory Verbal Learning Test was the best predictor of Aβ status among the psychometric tests, achieving an AUC of 0.67 ± 0.02 and odds ratio of 2.5 ± 0.4. FDG-PET was the best imaging-based biomarker (AUC 0.67 ± 0.03, OR 3.2 ± 1.2), followed by hippocampal volume (AUC 0.64 ± 0.02, OR 2.4 ± 0.3). A multivariate analysis based on the psychometric tests improved on the univariate predictors, achieving an AUC of 0.68 ± 0.03 (OR 3.38 ± 1.2). Adding imaging biomarkers to the multivariate analysis did not improve the AUC. Psychometric tests perform as well as imaging biomarkers to predict presence of molecular markers of AD pathology in MCI patients and should be considered in the determination of the likelihood that MCI is due to AD.

White matter signal abnormality quality differentiates mild cognitive impairment that converts to Alzheimer's disease from nonconverters

The objective of this study was to assess how longitudinal change in the quantity and quality of white matter signal abnormalities (WMSAs) contributes to the progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD). The Mahalanobis distance of WMSA from normal-appearing white matter using T1-, T2-, and proton density–weighted MRI was defined as a quality measure for WMSA. Cross-sectional analysis of WMSA volume in 104 cognitively healthy older adults, 116 individuals with MCI who converted to AD within 3 years (mild cognitive impairment converter [MCI-C]), 115 individuals with MCI that did not convert in that time (mild cognitive impairment nonconverter [MCI-NC]), and 124 individuals with AD from the Alzheimer's Disease Neuroimaging Initiative revealed that WMSA volume was substantially greater in AD relative to the other groups but did not differ between MCI-NC and MCI-C. Longitudinally, MCI-C exhibited faster WMSA quality progression but not volume compared with matched MCI-NC beginning 18 months before MCI-C conversion to AD. The strongest difference in rate of change was seen in the time period starting 6 months before MCI-C conversion to AD and ending 6 months after conversion (p < 0.001). The relatively strong effect in this time period relative to AD conversion in the MCI-C was similar to the relative rate of change in hippocampal volume, a traditional imaging marker of AD pathology. These data demonstrate changes in white matter tissue properties that occur within WMSA in individuals with MCI that will subsequently obtain a clinical diagnosis of AD within 18 months. Individuals with AD have substantially greater WMSA volume than all MCI suggesting that there is a progressive accumulation of WMSA with progressive disease severity, and that quality change predates changes in this total volume. Given the timing of the changes in WMSA tissue quality relative to the clinical diagnosis of AD, these findings suggest that WMSAs are a critical component for this conversion and are a critical component of this clinical syndrome.

Quantitative measurement of [Na+] and [K+] in postmortem human brain tissue indicates disturbances in subjects with Alzheimer's disease and dementia with Lewy bodies.

Alzheimer's disease (AD) is associated with significant disturbances in the homeostasis of Na+ and K+ ions as well as reduced levels of Na+/K+ ATPase in the brain. This study used ICP-MS to accurately quantify Na+ and K+ concentrations in human postmortem brain tissue. We analyzed parietal cortex (Brodmann area 7) from 28 cognitively normal age-matched controls, 15 cases of moderate AD, 30 severe AD, and 15 dementia with Lewy bodies (DLB). Associations were investigated between [Na+] and [K+] and a number of variables including diagnosis, age, gender, Braak tangle stage, amyloid-β (Aβ) plaque load, tau load, frontal tissue pH, and APOE genotype. Brains from patients with severe AD had significantly higher (26%; p < 0.001) [Na+] (mean 65.43 ± standard error 2.91 mmol/kg) than controls, but the concentration was not significantly altered in moderate AD or DLB. [Na+] correlated positively with Braak stage (r = 0.45; p < 0.0001), indicating association with disease severity. [K+] in tissue was 10% lower (p < 0.05) in moderate AD than controls. However, [K+] in severe AD and DLB (40.97 ± 1.31 mmol/kg) was not significantly different from controls. There was a significant positive correlation between [K+] and Aβ plaque load (r = 0.46; p = 0.035), and frontal tissue pH (r = 0.35; p = 0.008). [Na+] was not associated with [K+] across the groups, and neither ion was associated with tau load or APOE genotype. We have demonstrated disturbances of both [Na+] and [K+] in relation to the severity of AD and markers of AD pathology, although it is possible that these relate to late-stage secondary manifestations of the disease pathology.

Redox proteomics analysis of HNE-modified proteins in Down syndrome brain: clues for understanding the development of Alzheimer disease

Down syndrome (DS) is the most common genetic cause of intellectual disability, due to partial or complete triplication of chromosome 21. DS subjects are characterized by a number of abnormalities including premature aging and development of Alzheimer disease (AD) neuropathology after approximately 40 years of age. Several studies show that oxidative stress plays a crucial role in the development of neurodegeneration in the DS population. Increased lipid peroxidation is one of the main events causing redox imbalance within cells through the formation of toxic aldehydes that easily react with DNA, lipids, and proteins. In this study we used a redox proteomics approach to identify specific targets of 4-hydroxynonenal modifications in the frontal cortex from DS cases with and without AD pathology. We suggest that a group of identified proteins followed a specific pattern of oxidation in DS vs young controls, probably indicating characteristic features of the DS phenotype; a second group of identified proteins showed increased oxidation in DS/AD vs DS, thus possibly playing a role in the development of AD. The third group of comparison, DS/AD vs old controls, identified proteins that may be considered specific markers of AD pathology. All the identified proteins are involved in important biological functions including intracellular quality control systems, cytoskeleton network, energy metabolism, and antioxidant response. Our results demonstrate that oxidative damage is an early event in DS, as well as dysfunctions of protein-degradation systems and cellular protective pathways, suggesting that DS subjects are more vulnerable to oxidative damage accumulation that might contribute to AD development. Further, considering that the majority of proteins have been already demonstrated to be oxidized in AD brain, our results strongly support similarities with AD in DS.

Virological and Immunological Characteristics of Human Cytomegalovirus Infection Associated With Alzheimer Disease

Serum, cerebrospinal fluid (CSF), and cryopreserved lymphocytes from subjects in the Rush Alzheimer's Disease Center Religious Orders Study were analyzed for associations between cytomegalovirus (CMV) infection and clinical and pathological markers of Alzheimer disease. CMV antibody levels were associated with neurofibrillary tangles (NFTs). CSF interferon γ was only detected in seropositive subjects and was significantly associated with NFTs. The percentage of senescent T cells (CD4+ or CD8+CD28-CD57+) was significantly higher for CMV-seropositive as compared to CMV-seronegative subjects and was marginally associated with the pathologic diagnosis of Alzheimer disease (CD4+) or amyloid-β (CD8+). Immunocytochemical analysis showed induction of amyloid-β in human foreskin fibroblasts (HFFs) infected with each of 3 clinical CMV strains. In the same subjects, there was no association of herpes simplex virus type 1 (HSV-1) antibody levels with CMV antibody levels or clinical or pathological markers of Alzheimer disease. HSV-1 infection of HFFs did not induce amyloid-β. These data support an association between CMV and the development of Alzheimer disease.

O2‐11‐05: Grey‐white matter contrast ratio relates to progression in mild cognitive impairment

Previous research suggests that grey and white matter contrast ratio (GWR) seen on MRI is significantly higher (healthier) in cognitively normal elders compared to individuals with Alzheimer's disease (AD) or mild cognitive impairment (MCI). We examined GWR and conversion status after a 3-year follow-up period in a small cohort of individuals with MCI. Data was analyzed on n = 138 participants from the Alzheimer's Disease Neuroimaging Initiative who met the following inclusion criteria: (1) baseline diagnosis of MCI; (2) 1.5T MRI acquisition on either a Siemens or GE scanner; (3) 36-month follow-up data. Participants, matched on Mini-Mental State Examination scores, were categorized into two groups according to their 36-month follow-up diagnoses: 1) non-converters (n = 69, 75 ± 7, 26% female), and 2) converters, who had an AD diagnosis at follow-up (n = 69, 75 ± 7, 30% female). FreeSurfer was used to generate GWR data using T1 structural MR images. For the GWR calculation, white matter was defined as 1mm below the grey-white boundary, and grey matter included 35% from the boundary through the cortex. GWR surfaces were smoothed prior to analyses. Higher GWR values represented better brain integrity (i.e., less degradation in tissue contrast). Using a general linear model with a threshold of P <0.01, converters evidenced significantly lower GWR values than non-converters (i.e., more degradation in tissue contrast), specifically within the left and right temporal lobe. Secondary analyses regressing out hippocampal volume (i.e., a proxy measure of AD pathology) increased the region of GWR significance in the left hemisphere, but attenuated the area of GWR significance in the right hemisphere. We observed differences in GWR between MCI individuals who convert to AD versus those individuals who remain diagnostically stable over a three-year period. Such differences persisted even after adjusting for a traditional neuroimaging marker of AD pathology (i.e., hippocampal volume). GWR may represent an early neuroimaging marker of abnormal brain aging that precedes AD pathology or a second pathway of brain injury independent of AD pathology. Future research is needed to better understand the pathological and clinical implications of GWR.

Grey matter volume correlates of cerebrospinal markers of Alzheimer-pathology in Parkinson's disease and related dementia

Regional brain grey matter volume (GMV) reductions and abnormal cerebrospinal fluid (CSF) levels of τ and Aβ, extensively studied as biomarkers of Alzheimer's disease (AD), have also been reported in Parkinson's disease (PD) and related dementia (PDD). However, the relationship between these CSF and MRI biomarkers in PD and PDD remains unexplored. We studied these associations in 33 PD patients (18 with no dementia [PDND]; 15 fulfilling PDD criteria) and 12 neurologically unimpaired controls, with neuropsychological assessment, CSF ELISA studies, and voxel-based morphometry (VBM) analysis of high-field brain MRI. Neuropsychological assessment showed a gradation in cognitive performance from controls to PDND (significantly worse on visuospatial performance) and then to PDD (more impaired on memory, naming, fluency and visuospatial functions). No CSF-VBM correlations were found in controls or PDND patients. In contrast, in the analysis of both the PDD subgroup and the entire PD (PDND + PDD) sample, we found significant negative CSF-GMV correlations for τ and phospho-τ and significant positive CSF-GMV correlations for Aβ in mostly frontal and temporal structures. The correlations in the entire PD sample fitted with a linear model and were thus unlikely to have been driven solely by the PDD subgroup. Additionally, an association between both the CSF markers and the CSF-associated GMV reductions with several neuropsychological functions was found. We interpret that CSF markers of AD pathology are associated with VBM-measures of brain atrophy in PD-related dementia and within the PD cognitive continuum, and deserve further attention as putative biomarkers of cognitive impairment and dementia in PD.

Early development of social deficits in APP and APP-PS1 mice

Mimicking relevant behavioral features of the human pathology is one of the most important challenges for animal models of neurological disorders including Alzheimer disease (AD). Indeed, the most popular genetic AD mouse lines bearing mutations of the amyloid precursor protein (APP) and presenilin 1 genes (PS1), often fail to present robust cognitive deficits or show them only at very advanced ages. It is therefore crucial to identify AD-like behavioral alterations which may reliably reflect the early stages of the pathology, thus permitting tests of more efficient early therapeutic interventions. Here, we demonstrated the very early expression of noncognitive AD-like symptoms, i.e., deficits in social interest, interaction and communication, in APP and APP-PS1 transgenic mice. Conversely, other noncognitive behaviors (sensori-motor gating) as well as cognitive abilities (spontaneous alternation) were unaltered in AD transgenics. Our data suggest that social deficits precede other neuropsychiatric and cognitive AD-like symptoms and can be employed as early markers of AD pathology in genetic mouse models.

The independent effects of white matter hyperintensity volume and cerebrospinal fluid amyloid levels on brain atrophy

Increased rates of brain atrophy are seen in Alzheimer's disease (AD) and in vascular dementia. The relative contribution of these pathologies is often unclear. Low CSF As1-42 is a marker of AD pathology while white matter hyperintensities (WMH) are thought to be due to vascular damage. The aim of this study was to investigate the relationship between atrophy, WMHs and CSF As1-42.

Triflusal reduces cerebral ischemia induced inflammation in a combined mouse model of Alzheimer's disease and stroke

Clinical data has shown that stroke exacerbates dementia in Alzheimer's disease (AD) patients. Previous work, combining rat models of AD and stroke have shown that neuroinflammation may be the common mediator between AD and stroke toxicity. This study examined the effects of triflusal (2-acetoxy-4-trifluoromethylbenzoic acid) in APP 23 transgenic mice receiving strokes. Six month-old APP 23 mice over-expressing mutant human amyloid precursor protein (APP) were used to model AD in this study. Unilateral injections of a potent vasoconstrictor, endothelin-1, into the striatum were used to mimic small lacunar infarcts. Immunohistochemical analysis was performed to examine AD-like pathology and inflammatory correlates of stroke and AD. APP 23 mice showed increases in AD-like pathology and inflammatory markers of AD in the cortex and hippocampus. Endothelin-induced ischemia triggered an inflammatory response along with increases in AD pathological markers in the region of the infarct. Triflusal reduced inflammation surrounding the endothelin-induced infarct only. At the dose used, anti-inflammatory treatment may be beneficial in reducing the AD and inflammatory correlates of stroke in a combined AD-stroke mouse model.

Differential levels of apolipoprotein E and butyrylcholinesterase show strong association with pathological signs of Alzheimer's disease in the brain in vivo

Recently, we reported that 3 of the known risk factors of Alzheimer's disease (AD), i.e., advanced age, apolipoprotein E (ApoE) ε4, and female gender, are associated with differential levels of ApoE proteins and butyrylcholinesterase (BuChE) in the cerebrospinal fluid (CSF) of AD patients. The ApoE ε4 allele and certain BuChE polymorphisms synergistically affect the conversion rate of mild cognitive impairment (MCI) to AD. Here, we investigated interrelationships between ApoE and BuChE levels, and pathological markers of AD in vivo. CSF from patients with probable AD, assessed for cerebral glucose metabolism (CMRglc; n = 50) and Pittsburgh compound B (PIB) retention (β-amyloid [Aβ] load, n = 29) by positron emission tomography (PET), was used for measurement of BuChE, ApoE, Aβ, tau, phosphorylated tau (P-tau) and interleukin-1β (IL-1β) levels. Levels of ApoE and BuChE strongly correlated with CMRglc (fluorodeoxyglucose [FDG]-PET, r = 0.54, p < 0.0001, n = 50), cerebral Aβ load (PIB retention, r = 0.73, p < 0.0001, n = 29), and CSF P-tau (r = 0.73, p < 0.0001, n = 33). High ApoE protein was tied to low CMRglc and high PIB retention and P-tau. BuChE levels had opposite relationships. Other CSF covariates were levels of interleukin-1β and Aβ(42) peptide. The pattern of the patients' cognitive Z-scores strongly supported these observations. High ApoE protein was also linked to changes in 3 of the biodynamic properties of BuChE. In vitro analysis indicated that high ApoE protein levels were related to an increased pool of dormant BuChE molecules with an abnormally high intrinsic catalytic rate in CSF, which was "turned on" by excess Aβ peptides. The findings suggest that abnormally high levels of ApoE may play a causative role in the pathological events of AD, particularly those involving the early cholinergic deficit in the AD brain, through modulation of cholinesterases activities, hence disturbing the acetylcholine-dependent activity of neurons and nonexcitable cells such as glial cells.

BACE1 Activity in Cerebrospinal Fluid and Its Relation to Markers of AD Pathology

Several studies have shown that reduced amyloid-beta 1-42 (Abeta(42)) and increased tau levels in cerebrospinal fluid (CSF) reflect increased Alzheimer's disease (AD) pathology in the brain. beta-site APP cleaving enzyme (BACE1) is thought to be the major beta-secretase involved in Abeta production in the brain, and therefore we investigated the relation between BACE1 activity and CSF markers Abeta(40), Abeta(42), total tau (t-tau), and tau phosphorylated at threonine 181 (p-tau) in CSF of control (n=12), mild cognitive impairment (n=18), and AD (n=17) subjects. Patients were classified according to their Abeta(42), t-tau, and p-tau CSF biomarker levels, with either an AD-like biomarker profile (two or three biomarkers abnormal: Abeta(42) < 495 pg/ml in combination with t-tau > 356 pg/ml, and/or p-tau > 54 pg/ml) or a normal biomarker profile (<or= one biomarker abnormal). This resulted in 19 subjects with an AD-like biomarker profile (66 +/- 6 years, 53% female, and Mini-Mental Status Examination (MMSE) score: 23 +/- 5) and 28 subjects with a normal biomarker profile (62 +/- 11 years, 43% female, and MMSE score: 27 +/- 4). Subjects with an AD-like biomarker profile had higher CSF BACE1 activity levels, compared to patients with a normal biomarker profile (20 pg/ml and 16 pg/ml respectively; p=0.01), when controlled for age and gender. In the whole sample, BACE1 activity correlated with CSF levels of Abeta(40), t-tau, and p-tau (r=0.38, r=0.63, and r=0.65; all p< 0.05), but not with Abeta(42). These data suggest that increased BACE1 activity in CSF relates to AD pathology in the brain.

Detecting Alzheimer disease before it happens

Although consensus is rare in the Alzheimer disease (AD) research community, there is widespread agreement that the development of AD prevention strategies is of paramount importance. However, primary prevention trials relying on clinical outcome measures are exceedingly time and labor-intensive, requiring thousands of subjects followed over several years. One approach to accelerating the process is to validate surrogate markers of AD pathology for use in prevention studies. Three surrogate markers, namely CSF total tau, phosphorylated tau, and the lipid peroxidation product F2-isoprostanes, have been identified and validated as markers that are elevated in CSF in established AD,1 while CSF beta amyloid (Aβ)1-42 is lower in established AD compared to control subjects.1 The sensitivity of these CSF markers for detecting presymptomatic pathologic changes, however, has not been established. The utility of plasma levels of these biomarkers is less clear. Tau and p-tau are not measurable in plasma, while Aβ and isoprostanes are detectable in picomolar concentrations. Reports on the ability of systemic isoprostanes to distinguish AD from control subjects are not consistent. …

Delayed rather than decreased BOLD response as a marker for early Alzheimer's disease

Functional MRI (fMRI) in established Alzheimer's disease (AD) shows regionally altered blood oxygenation level dependent (BOLD) responses. Mild cognitive impairment (MCI) is thought to represent an intermediate state between health and early Alzheimer's disease. To study this probable early dementia stage pathology, we studied in detail the BOLD response in MCI during visual encoding. 28 MCI patients, 18 AD patients, and 41 healthy elderly controls performed a face encoding task during fMRI scanning. Data were analyzed using orthogonal regressors, each representing different phases of the BOLD response (from slow to fast). Using a mixed effects model, regressor × group interactions were analyzed applying P < 0.05, corrected. In occipital regions, MCI patients could be distinguished significantly better from controls and AD patients with a regressor of the early phase of the (fast) BOLD response than with the regressor of the late (slow) BOLD phase. Occipitally, the early phase BOLD response was significantly diminished in MCI patients compared to controls, and significantly increased when compared to AD. AD patients showed diminished early phase activation in widespread regions throughout the brain when compared to controls. There were no differences in the late (slow) phase of the BOLD response. This study stresses the importance of analyzing early phase BOLD responses and not only using one model of the BOLD response in neurodegenerative diseases. The increasing delay of the BOLD response from controls to MCI to AD may be consistent with the idea that MCI is a transitional state between healthy aging and dementia. Analyzing differences in different phases of the BOLD response introduces new opportunities to understand changes in regional brain dynamics in MCI and how well this may serve as an early marker of AD pathology.

A plasticity-based theory of the pathogenesis of Alzheimer's disease.

Amyloid plaques (APs) and neurofibrillary tangles (NFTs) are the two diagnostic markers of Alzheimer's disease (AD). The neuropsychological features of AD are closely correlated with the distribution of the NFTs and therefore favor a disease process revolving around neurofibrillary degeneration. The genetics, however, favor a disease process revolving around the APs, principally because mutations in the amyloid precursor protein (A beta PP) are sufficient to cause AD. The inability to reconcile these two aspects of AD has prevented the formulation of a unified theory of pathogenesis. It is interesting to note that all genetic causes and risk factors of AD can increase the physiological burden of neuroplasticity. My hypothesis is that the resultant intensification of the plasticity burden leads to an initially adaptive upregulation of tau phosphorylation and A beta PP turnover, to the subsequent formation of NFTs and APs as independent consequences of excessive plasticity-related cellular activity, and to the eventual loss of neurons, dendrites, and synapses as the ultimate expression of plasticity failure. The two pathological markers of AD are therefore independent manifestations of a more fundamental process through which the many different genotypes of AD trigger an identical clinical and neuropathological phenotype.