Non-demented Elderly Controls Research Articles

Comparative study of Raman spectroscopy techniques in blood plasma-based clinical diagnostics: A demonstration on Alzheimer’s disease

Nowadays, there are still many diseases with limited or no reliable methods of early diagnosis. A popular approach in clinical diagnostic research is Raman spectroscopy, as a relatively simple, cost-effective, and high-throughput method for searching for disease-specific alterations in the composition of blood plasma. However, the high variability of the experimental designs, targeted diseases, or statistical processing in the individual studies makes it challenging to compare and compile the results to critically assess the applicability of Raman spectroscopy in real clinical practice. This study aimed to compare data from a single series of blood plasma samples of patients with Alzheimer’s disease and non-demented elderly controls obtained by four different techniques/experimental setups – Raman spectroscopy with excitation at 532 and 785 nm, Raman optical activity, and surface-enhanced Raman scattering spectroscopy. The obtained results showed that the spectra from each Raman spectroscopy technique contain different information about biomolecules of blood plasma or their conformation and may, therefore, offer diverse points of view on underlying biochemical processes of the disease. The classification models based on the datasets generated by the three non-chiroptical variants of Raman spectroscopy exhibited comparable diagnostic performance, all reaching an accuracy close to or equal to 80%. Raman optical activity achieved only 60% classification accuracy, suggesting its limited applicability in the specific case of Alzheimer’s disease diagnostics. The described differences in the outputs of the four utilized techniques/setups of Raman spectroscopy imply that their choice may crucially affect the acquired results and thus should be approached carefully concerning the specific purpose.

CCR5 deficiency normalizes TIMP levels, working memory, and gamma oscillation power in APOE4 targeted replacement mice

The APOE4 allele increases the risk for Alzheimer's disease (AD) in a dose-dependent manner and is also associated with cognitive decline in non-demented elderly controls. In mice with targeted gene replacement (TR) of murine APOE with human APOE3 or APOE4, the latter show reduced neuronal dendritic complexity and impaired learning. APOE4 TR mice also show reduced gamma oscillation power, a neuronal population activity which is important to learning and memory. Published work has shown that brain extracellular matrix (ECM) can reduce neuroplasticity as well as gamma power, while attenuation of ECM can instead enhance this endpoint. In the present study we examine human cerebrospinal fluid (CSF) samples from APOE3 and APOE4 individuals and brain lysates from APOE3 and APOE4 TR mice for levels of ECM effectors that can increase matrix deposition and restrict neuroplasticity. We find that CCL5, a molecule linked to ECM deposition in liver and kidney, is increased in CSF samples from APOE4 individuals. Levels of tissue inhibitor of metalloproteinases (TIMPs), which inhibit the activity of ECM-degrading enzymes, are also increased in APOE4 CSF as well as astrocyte supernatants brain lysates from APOE4 TR mice. Importantly, as compared to APOE4/wild-type heterozygotes, APOE4/CCR5 knockout heterozygotes show reduced TIMP levels and enhanced EEG gamma power. The latter also show improved learning and memory, suggesting that the CCR5/CCL5 axis could represent a therapeutic target for APOE4 individuals.

Distinct changes in all major components of the neurovascular unit across different neuropathological stages of Alzheimer's disease.

In the brain capillaries, endothelial cells, pericytes, astrocytes and microglia form a structural and functional complex called neurovascular unit (NVU) which is critically involved in maintaining neuronal homeostasis. In the present study, we applied a comprehensive immunohistochemical approach to investigate the structural alterations in the NVU across different Alzheimer's disease (AD) neuropathological stages. Post-mortem human cortical and hippocampal samples derived from AD patients and non-demented elderly control individuals were immunostained using a panel of markers representing specific components of the NVU including Collagen IV (basement membrane), PDGFR-β (pericytes), GFAP (astrocytes), Iba1 (microglia), MRC1 (perivascular macrophages) and lectin as an endothelial cell label. Astrocytes (GFAP) and microglia (Iba1) were quantified both in the whole visual-field and specifically within the NVU, and the sample set was additionally analyzed using anti-tau (AT8) and three different anti-Aβ (clones G2-10, G2-11, 4G8) antibodies. Analyses of lectin labeled sections showed an altered vascular distribution in AD patients as revealed by a reduced nearest distance between capillaries. Within the NVU, a Braak-stage dependent reduction in pericyte coverage was identified as the earliest structural alteration during AD progression. In comparison to non-demented elderly controls, AD patients showed a significantly higher astrocyte coverage within the NVU, which was paralleled by a reduced microglial coverage around capillaries. Assessment of perivascular macrophages moreover demonstrated a relocation of these cells from leptomeningeal arteries to penetrating parenchymal vessels in AD patients. Collectively, the results of our study represent a comprehensive first in-depth analysis of AD-related structural changes in the NVU and suggest distinct alterations in all components of the NVU during AD progression.

Diagnostic Accuracy of ELISA and Luminex Technology (xMAP) for the Quantitation of CSF Amyloid Beta 40 and 42 Peptides to differentiate Patients with Probable Alzheimer Disease (AD) from Elderly Non-demented Controls (P1.094)

Diagnostic Accuracy of ELISA and Luminex Technology (xMAP) for the Quantitation of CSF Amyloid Beta 40 and 42 Peptides to differentiate Patients with Probable Alzheimer Disease (AD) from Elderly Non-demented Controls (P1.094)

ApoE genotyping by DNA microarray assay and the relationship between ApoE allelic frequency and serum ApoE levels

Objective To investigate the application value of apolipoprotein E (ApoE) genotyping by DNA microarray technology and the relationship between ApoE allelic frequency and serum ApoE levels in both healthy individuals and patients with Alzheimer's disease (AD). Methods This research is case-control study. DNA microarray was used to detect the ApoE genotypes of AD patients (n=280) and age-matched non-demented elderly control subjects (n=230). The cases and controls were collected in Guangzhou Huiai Hospital during July 2014 to September 2015. The accuracy of genotype results was verified by DNA sequencing. Serum ApoE levels were measured by immunoturbidimetric assay. The ApoE genotype distribution and the relationship between ApoE allelic frequency and serum ApoE levels were analyzed.The t test was used to compare the ApoE levels of AD patients and controls, variance analysis was used to analyze ApoE levels in the persons with different genotype. Results DNA microarray technology genotyping results were completely consistent with the results of DNA sequencing. In AD group, the ApoE genotype distribution were 2.9%(8/280) for e2e3, 1.8% (5/280)for e2e4, 46.8% (131/280)for e3e3, 45.4%(127/280)for e3e4 and 3.1%(9/280) for e4e4.While in the control group, the ApoE genotype distribution were 0.9%(2/230) for e2e2, 12.6% (29/230)for e2e3, 1.3%(3/230) for e2e4, 70.0% (161/230)for e3e3 and 15.2% (35/230)for e3e4. The average serum concentrations of ApoE were (33.29±10.87)mg/L in AD patients and (41.28±10.95)mg/L in the controls. Among all participants, the average serum levels of ApoE were (50.86±6.21)mg/L for e2 carriers, (38.78±12.07)mg/L for e3 carriers and (30.47±7.68)mg/L for e4 carriers. In AD group, ApoE level of e2, e3, e4 carriers is (50.31±9.08)mg/L, (38.30±7.60) mg/L and (32.86±5.93)mg/L respectively. In the control group, the ApoE level of e2, e3, e4 carriers is (51.00±5.53)mg/L, (41.01±10.09)mg/L and (32.86±5.93)mg/L respectively. The ApoE levels of persons with different ApoE alleles are e2>e3>e4. The difference is significant (F=89.6, P 0.05). Conclusions DNA microarray technology possesses high efficiency and favorable accuracy. The e2 allele is associated with a higher ApoE concentration, e3 allele with a mediate concentration and e4 allele with a lowest concentration. Serum concentrations of ApoE showed no significant difference between AD patients and the healthy groups who have the same genotype. The primary cause of the low serum ApoE levels in AD patients is that the ApoE e4 allelic frequencies of them are higher than that of the healthy persons.(Chin J Lab Med, 2016, 39: 506-510) Key words: Alzheimer disease; Apolipoproteins E; Genotype; Sequence analysis, DNA; Microarray analysis

Benzodiazepine Use Attenuates Cortical β-Amyloid and is Not Associated with Progressive Cognitive Decline in Nondemented Elderly Adults: A Pilot Study Using F18-Florbetapir Positron Emission Tomography

It is inconclusive as to whether benzodiazepines (BZDs) are related to cognitive deterioration in the elderly populations. Animal studies suggest that γ-aminobutyric acid A receptor agonists, such as BZDs, may prevent Aβ-neurotoxicity and reduce β-amyloid (Aβ). However, no studies have investigated the effects of BZD use on Aβ in humans. This cross-sectional, prospective study using Alzheimer's Disease Neuroimaging Initiative sites in the United States and Canada on nondemented elderly adults between 55 and 90 years of age assessed cortical Aβ levels by positron emission tomography radiotracer F18-Florbetapir. Changes in global cognitive function and verbal memory performance over 2 years were assessed using scores on Montreal Cognitive Assessment and five domains of Rey Auditory Verbal Learning Test, respectively. Previous BZD users (N = 15) had lower cortical Aβ levels in frontal (F(1, 26) = 8.82, p = 0.006), cingulate (F(1, 26) = 8.58, p = 0.007), parietal (F(1, 26) = 7.31, p = 0.012), and temporal (F(1, 26) = 7.67, p = 0.010) regions compared with matched BZD nonusers (N = 15), after controlling for history of psychiatric disorders and antidepressant use. Also, no differences were found in global cognitive function and changes in cortical Aβ over 2 years between continuous BZD users (N = 15) andthe matched nonuser group (N = 15). Previous BZD use was associated with lower cortical Aβ levels in nondemented elderly control subjects. Future studies with larger samples are required to replicate our findings.

Comparison of Metal Levels between Postmortem Brain and Ventricular Fluid in Alzheimer's Disease and Nondemented Elderly Controls.

An essential metal hypothesis for neurodegenerative disease suggests an alteration in metal homeostasis contributing to the onset and progression of disease. Similar associations have been proposed for nonessential metals. To examine the relationship between metal levels in brain tissue and ventricular fluid (VF), postmortem samples of frontal cortex (FC) and VF from Alzheimer's disease (AD) cases and nondemented elderly subjects were analyzed for arsenic (As), cadmium (Cd), chromium (Cr), cobalt (Co), copper (Cu), iron (Fe), lead (Pb), manganese (Mn), mercury (Hg), nickel (Ni), tin (Sn), vanadium (V), and zinc (Zn) using inductively coupled plasma sector field mass spectrometry. All metals, with exception of equivalent Pb levels, were lower in the VF, compared to FC. Within-subject comparisons demonstrated that VF levels were not representative of levels within brain tissue. The essential metals Cu, Fe, and Zn were found highest in both compartments. Cd, Hg, and V levels in the VF were below the limit of quantification. In AD cases, FC levels of Fe were higher and As and Cd were lower than levels in controls, while levels of As in the VF were higher. Parameter estimates for FC metal levels indicated an association of Braak stage and higher Fe levels and an association of Braak stage and lower As, Mn, and Zn levels. The data showed no evidence of an accumulation of nonessential metals within the AD brain and, with the exception of As, showed no significant shift in the ratio of FC to VF levels to indicate differential clearance.

Characterization of Early Pathological Tau Conformations and Phosphorylation in Chronic Traumatic Encephalopathy.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy that develops after repetitive head injury. Several lines of evidence in other tauopathies suggest that tau oligomer formation induces neurotoxicity and that tau oligomer-mediated neurotoxicity involves induction of axonal dysfunction through exposure of an N-terminal motif in tau, the phosphatase-activating domain (PAD). Additionally, phosphorylation at serine 422 in tau occurs early and correlates with cognitive decline in patients with Alzheimer disease (AD). We performed immunohistochemistry and immunofluorescence on fixed brain sections and biochemical analysis of fresh brain extracts to characterize the presence of PAD-exposed tau (TNT1 antibody), tau oligomers (TOC1 antibody), tau phosphorylated at S422 (pS422 antibody), and tau truncated at D421 (TauC3 antibody) in the brains of 9-11 cases with CTE and cases of nondemented aged controls and AD (Braak VI) (n = 6, each). All 3 early tau markers (ie, TNT1, TOC1, and pS422) were present in CTE and displayed extensive colocalization in perivascular tau lesions that are considered diagnostic for CTE. Notably, the TauC3 epitope, which is abundant in AD, was relatively sparse in CTE. Together, these results provide the first description of PAD exposure, TOC1 reactive oligomers, phosphorylation of S422, and TauC3 truncation in the tau pathology of CTE.

Identification of Pivotal Markers in Vascular Dementia Based on Proteomics Data

Objective: The aim of this study was to analyze protein expression profiles of vascular dementia (VaD) subjects for investigating the underlying therapeutic markers. Methods: Protein expression profile data were acquired from a quantitative clinical proteomic study, including 10 nondemented elderly controls and 10 age-matched VaD subjects. Differentially expressed proteins (DEPs) were identified between VaD subjects and controls, followed by function prediction using DAVID (Database for Annotation, Visualization, and Integrated Discovery). Then, a protein-protein interaction (PPI) network was constructed by comparing it with the STRING (Search Tool for the Retrieval of Interacting Genes) database, and the pathway crosstalk analysis was conducted based on overlapping PPI network and enriched pathways. Furthermore, the subpathway was screened and analyzed by the iSubpathwayMiner package in R. Results: A total of 144 DEPs were screened from VaD subjects and the controls. They were significantly enriched in many pathways. High-degree proteins were detected in the PPI network, such as ATP5B (ATP synthase subunit β). Furthermore, ‘metabolic pathways' and ‘Alzheimer's disease' were the significant pathways screened in the crosstalk analysis. At last, upregulated proteins were enriched in 2 subpathways of 1 pathway, while downregulated proteins were enriched in 162 subpathways of 36 pathways. Conclusion: By analyzing the differential expressions of proteins, the potential underlying therapeutic markers and mechanism of VaD might be elucidated.

A Complex Association of ABCA7 Genotypes With Sporadic Alzheimer Disease in Chinese Han Population

Recently, a large genome-wide association study has revealed that polymorphism of alleles and genotypes in rs3,764,650 within ABCA7 gene is associated with Alzheimer disease in whites. We conducted a case-control study to investigate whether these susceptible genetic variants are risk factors for sporadic Alzheimer disease (SAD) in Chinese Han population. A total of 633 participants consisting of 350 SAD and 283 nondemented elderly controls matched for sex and age were recruited and genetic variants in ABCA7 (rs3,764,650) were genotyped using DNA sequencing. On the basis of allele and genotype frequencies in both groups, we found a significant association (P=0.004) between ABCA7 genotypes and SAD in Chinese Han population, and the results were influenced by age and ApoEε4 status. ApoEε4-carrier and aging are linked to enhancing ABCA7 risk-associated SAD. However, the prevalence of the minor allele G in rs3,764,650 within ABCA7 showed no significant difference between the 2 groups in this study. ABCA7 (rs3,764,650) was associated with SAD in the Chinese population, with both ApoEε4-carrier and aging being factors enhancing its risk.

Both Targeted Mass Spectrometry and Flow Sorting Analysis Methods Detected the Decreased Serum Apolipoprotein E Level in Alzheimer's Disease Patients

Apolipoprotein E (ApoE) polymorphism has been appreciated as a valuable predictor of Alzheimer disease (AD), and the associated ε4 allele has been recognized as an indicator of susceptibility to this disease. However, serum ApoE levels have been a controversial issue in AD, due to the great variability regarding the different target detection methods, ethnicity, and the geographic variations of cohorts. The aim of this study was to validate serum ApoE levels in relation to AD, particularly using two distinct detection methods, liquid chromatography-selected reaction monitoring (SRM) mass spectrometry and microsphere-based fluorescence-activated cell sorting (FACS) analysis, to overcome experimental variations. Also, comparison of serum ApoE levels was performed between the level of protein detection by FACS and peptide level by SRM in both control and AD patients. Results from the two detection methods were cross-confirmed and validated. Both methods produced fairly consistent results, showing a significant decrease of serum ApoE levels in AD patients relative to those of a control cohort (43 control versus 45 AD, p < 0.0001). Significant correlation has been revealed between results from FACS and SRM (p < 0.0001) even though lower serum ApoE concentration values were measured in protein by FACS analysis than in peptide-level detections by SRM. Correlation study suggested that a decrease of the serum ApoE level in AD is related to the mini-mental state exam score in both results from different experimental methods, but it failed to show consistent correlation with age, gender, or clinical dementia rating.

Smell identification function as a severity and progression marker in Alzheimer's disease

Olfactory dysfunction, impaired smell identification in particular, is known as a diagnostic and a marker of conversion in Alzheimer's disease (AD). We aimed to evaluate the associations of olfactory identification impairments with cognition, illness severity, and progression in AD patients. Fifty-seven outpatients with late onset mild to moderate AD and 24 elderly non-demented controls (NDC) were assessed, at baseline and after three months, for Mini-Mental State Examination (MMSE), University of Pennsylvania Smell Identification Test (UPSIT), and Bristol Activities of Daily Living and Neuropsychiatry Inventory. AD participants were classified as Rapid Cognitive Decliners (RCD) defined on a priori with a loss of ≥2 points in MMSE within the previous six months. AD participants had lower olfactory scores than NDC. RCD had lower olfaction scores compared with Non-Rapid Cognitive Decliners (NRCD). Although the baseline UPSIT scores were associated with baseline MMSE scores, it did not interact significantly with change in MMSE over the follow-up period. Using a median split for olfactory scores, the AD participants were classified as Rapid Olfactory Progressors (ROP) (UPSIT ≤ 15) and Slow Olfactory Progressors correlating significantly with RCD/NRCD groups. The ROP group with higher olfactory impairment indicated more symptomatic illness or severity, i.e. lower cognition, higher functional dependence, and presence of behavioral symptoms. Our study supports association of smell identification function with cognition and its utility as an adjunct clinical measure to assess severity in AD. Further work, including larger longitudinal studies, is needed to explore its value in predicting AD progression.

Increased skin temperature in Alzheimer’s disease is associated with sleepiness

The 24-h rhythms in sleep and temperature both change in Alzheimer's disease (AD). Characteristic changes consist of a more fragmented diurnal sleep profile with frequent nocturnal awakenings and daytime sleepiness, as well as a reduction in the amplitude of the 24-h rhythm in core body temperature (CBT). Although the 24-h rhythm in CBT is to a large extent the result of a 24-h rhythm in heat loss from the skin caused by pronounced changes in skin blood flow and consequently skin temperature (Ts), changes in the diurnal skin temperature profile in AD as compared to normal aging have remained unexplored. Because recent work indicates a causal contribution of fluctuations in skin temperature to daytime sleepiness and nocturnal sleep depth, the present study aimed to investigate the skin temperature rhythm in AD and its association with daytime sleepiness and nocturnal sleep. Ambulatory recorders were used to estimate sleep and 24-h rhythms in skin temperature in 55 AD patients and 26 matched non-demented elderly controls. Subjective sleep and daytime sleepiness were obtained using questionnaires. The results indicate that AD patients had a significantly higher daytime proximal skin temperature (PST) than elderly controls. In both AD patients and elderly controls, an elevated daytime PST was associated with more daytime sleepiness. The findings suggest a deficient downregulation of daytime proximal skin blood flow that might contribute to daytime sleepiness. Because daytime sleepiness contributes to cognitive dysfunction in AD, further research into the underlying mechanisms and possible reversibility is warranted.

Telomere length shortening in patients with dementia with Lewy bodies

Shortened telomere length has been considered to be associated with various age-related diseases, especially in dementia such as Alzheimer's disease and vascular dementia. However, changes in telomere length in dementia with Lewy bodies (DLB) remain unclear. To elucidate these changes, we set out to determine telomere length in peripheral leukocytes as well as the level of urinary 8-hydroxy-deoxyguanosine (8-OHdG) as a marker of oxidative stress in DLB. Blood samples were obtained from 33 patients with a clinical diagnosis of probable DLB and 35 age-matched, non-demented elderly controls (NEC). Telomere length was assessed by quantitative real-time polymerase chain reaction of genomic DNA extracted from leukocytes, whereas oxidative stress was assessed on the basis of urine 8-OHdG level, which was measured using high-performance liquid chromatography. Telomere length was significantly shorter in the DLB group than in the NEC group. Urinary 8-OHdG levels were significantly higher in the DLB group than in the NEC group. There was a negative correlation between telomere length and age in the DLB group; however, there were no significant relationships between telomere length and clinical findings including disease duration, severity of cognitive decline, presence or absence of fluctuation in cognitive function, visual hallucinations, and Parkinsonism. In both groups, the correlation between telomere length and urinary 8-OHdG levels was not significant. These findings indicate that the etiopathology of DLB is considered to be an accelerated aging process.

Elevated labile Cu is associated with oxidative pathology in Alzheimer disease

Oxidative stress is implicated in Alzheimer disease (AD) pathogenesis, for which evidence indicates that radical species are generated by the redox-active biometal Cu. The contribution of labile Cu to the oxidative stress observed in AD has not been evaluated. The Cu content of postmortem cortical tissue from nondemented elderly controls and AD cases was measured using inductively coupled plasma mass spectroscopy, and the proportion of labile Cu was assessed using the Cu–phenanthroline assay. Further, the capacity of the tissue to stabilize Cu 2+ was evaluated using immobilized metal-affinity chromatography, and the level of tissue oxidative damage was determined by the presence of thiobarbituric acid-reactive compounds. We identified elevated levels of exchangeable Cu 2+, which were correlated with tissue oxidative damage; additionally, we noted an increased capacity of AD cortical tissue samples to bind Cu 2+. This deranged Cu homeostasis reflects the homeostatic breakdown of Cu observed in AD and supports biometal metabolism as a therapeutic target.

Preserved and impaired task‐switching abilities in non‐demented patients with Parkinson's disease

Existing studies on task switching in Parkinson's disease (PD) patients have led to somewhat different results. In particular, it is unclear whether PD patients have a deficit in attentional control. In this study, we assessed task-switching abilities in samples of non-demented PD patients and elderly controls. We used a paradigm in which there was a random task sequence and the task was cued in every trial. This allowed the investigation of both task-set reconfiguration and task-set dissipation. In terms of the proportion of errors made, the patients showed increased switch cost and congruency effects. For reaction times, PD patients showed enlarged congruency effects on switch trials, specifically in the condition in which we used a short constant response-cue interval (RCI). Nevertheless, in a similar fashion to older controls, the patients showed reductions in reaction time switch cost from a short to a long cue-target interval (CTI) and from a short to a long RCI. While these latter findings, respectively, suggest unimpaired task preparation and task dissipation on correct trials in the PD patients, the overall results show that they have a deficit in biasing and selecting currently relevant task sets and more generally argue in favour of a failure of attentional control in PD.

Quantitation of plasma Abeta40 and Abeta42 levels using rabbit monoclonal antibodies

Previously we quantitated plasma Abeta40 and Abeta42 levels using a combination of mouse monoclonal antibody 6E10 as a capture antibody and rabbit polyclonal antibodies specific to Abeta as detection antibodies. Recently, we have produced rabbit monoclonal antibodies (Rabmab) to Abeta40 and Abeta42. Currently there is a great interest in the measurement of plasma Abeta levels at intervals in AD and elderly non-demented controls. Reports showed conflicting data and the reason is not known. We hypothesize that differences in antibody epitopes and affinity may have contributed to the variable findings. We examined 40 AD or control plasma samples using 1) a combination of Rabmab to Abeta as capture antibodies and 4G8 mouse monoclonal antibody as detecting antibody; and 2) mouse monoclonal antibody 6E10 as a capture antibody and Rabmab to Abeta as detecting antibodies in sandwich ELISA. There was a significant relation between Abeta40 levels of Rabmab to Abeta40 and rabbit polyclonal antibody to Abeta40 using 4G8 as detecting antibody (r = .67; p < 0.001), and Rabmab to Abeta42 and rabbit polyclonal antibody to Abeta42 using 4G8 as detecting antibody (r = .97; p < 0.001). Similarly there was a relation between Abeta levels using mouse monoclonal antibody 6E10 as capture antibody and Rabmab or polyclonal antibody as detecting antibodies. When the relationship between the levels using 4G8 and 6E10 were compared, there was a significant relation in Abeta40 levels (r = .63; p < .001) but not in Abeta42 levels (r = .19; p < .24). The data show that differences in capture or detecting antibodies may contribute to different findings among published studies.

Intracranial volume and dementia: Some evidence in support of the cerebral reserve hypothesis

The brain reserve hypothesis has been posited as being one important mediating factor for developing dementia, especially Alzheimer's disease (AD). Evidence for this hypothesis is mixed though different methodologies have made these findings difficult to interpret. We examined imaging data from a large cohort (N=194) of mixed dementia patients and controls, 65years old and older from the Cache County, Utah Study of Memory and Aging for evidence of the brain reserve hypothesis using total intracranial volume (TICV) as a quantitative measure of pre-morbid brain size and a vicarious indicator of reserve. A broader spectrum of non-demented elderly control subjects from previous studies was also included for comparison (N=423). In addition, non-parametric Classification and Regression Tree (CART) analyses were performed to model group heterogeneity and identify any subgroups of patients where TICV might be an important predictor of dementia. Parametrically, no main effect was found for TICV when predicting a dementia diagnosis; however, the CART analysis did reveal important TICV subgroups, including a sex differential wherein ε4 APOE allele presence in males and low TICV predicted AD classification. TICV, APOE, and other potential mediator/moderator variables are discussed in the context of the brain reserve hypothesis.

Bone Density and Brain Atrophy in Early Alzheimer's Disease

Studies suggest a link between bone loss and Alzheimer's disease. To examine bone mineral density (BMD) in early Alzheimer's disease (AD) and its relationship to brain structure and cognition, we evaluated 71 patients with early stage AD (Clinical Dementia Rating (CDR) 0.5 and 1) and 69 non-demented elderly control participants (CDR 0). Measures included whole body BMD by dual energy x-ray absorptiometry (DXA) and normalized whole brain volumes computed from structural MRI scans. Cognition was assessed with a standard neuropsychological test battery. Mean BMD was lower in the early AD group (1.11 +/- 0.13) compared to the non-demented control group (1.16 +/- 0.12, p = 0.02), independent of age, gender, habitual physical activity, smoking, depression, estrogen replacement, and apolipoprotein E4 carrier status. In the early AD group, BMD was related to whole brain volume (b = 0.18, p = 0.03). BMD was also associated with cognitive performance, primarily in tests of memory (logical memory [b = 0.15, p = 0.04], delayed logical memory [b = 0.16, p = 0.02], and the selective reminding task - free recall [b = 0.18, p = 0.009]). BMD is reduced in the earliest clinical stages of AD and associated with brain atrophy and memory decline, suggesting that central mechanisms may contribute to bone loss in early AD.

Proteomics-derived cerebrospinal fluid markers of autopsy-confirmed Alzheimer’s disease

The diagnostic performance of several candidate cerebrospinal fluid (CSF) protein biomarkers in neuropathologically confirmed Alzheimer’s disease (AD), non-demented (ND) elderly controls and non-AD dementias (NADD) was assessed. Candidate markers were selected on the basis of initial two-dimensional gel electrophoresis studies or by literature review. Markers selected by the former method included apolipoprotein A-1 (ApoA1), haemopexin (HPX), transthyretin (TTR) and pigment epithelium-derived factor (PEDF), while markers identified from the literature included Aβ1-40, Aβ1-42, total tau, phosphorylated tau, α-1 acid glycoprotein (A1GP), haptoglobin, zinc α-2 glycoprotein (Z2GP) and apolipoprotein E (ApoE). Ventricular CSF concentrations of the markers were measured by enzyme-linked immunosorbent assay (ELISA). The concentrations of Aβ1-42, ApoA1, A1GP, ApoE, HPX and Z2GP differed significantly among AD, ND and NADD subjects. Logistic regression analysis for the diagnostic discrimination of AD from ND found that Aβ1-42, ApoA1 and HPX each had significant and independent associations with diagnosis. The CSF concentrations of these three markers distinguished AD from ND subjects with 84% sensitivity and 72% specificity, with 78% of subjects correctly classified. By comparison, using Aβ1-42 alone gave 79% sensitivity and 61% specificity, with 68% of subjects correctly classified. For the diagnostic discrimination of AD from NADD, only the concentration of Aβ1-42 was significantly related to diagnosis, with a sensitivity of 58%, specificity of 86% and 86% correctly classified. The results indicate that for the discrimination of AD from ND control subjects, measurement of a set of markers including Aβ1-42, ApoA1 and HPX improved diagnostic performance over that obtained by measurement of Aβ1-42 alone. For the discrimination of AD from NADD subjects, measurement of Aβ1-42 alone was superior.