Non-demented Elderly Subjects Research Articles

The 18 kDa translocator protein is associated with microglia in the hippocampus of non-demented elderly subjects.

Increase in the brain expression of the 18 kDa translocator protein (TSPO) is considered as a marker of neuroinflammation in the context of brain diseases, such as Alzheimer's disease (AD). However, in non-demented subjects with Alzheimer's neuropathology, TSPO accumulation in hippocampus subdivisions has not been fully characterized. To determine if TSPO is associated with the presence of amyloid β plaques and/or phosphorylated Tau accumulation, we analyzed hippocampal sections using immunohistochemistry of 14 non-demented subjects with positive staining for Aβ and/or phosphorylated Tau. TSPO expression was heterogenous with higher accumulation in the CA2/3 and subiculum subfields of the hippocampus. Its distribution closely resembled that of the microglial IBA1 marker and of the Aβ42 amyloid form. In addition, positive correlations were observed between TSPO and IBA1 densities in CA4, CA2/3 and the subiculum but not with either the astrocyte GFAP marker or the AD-type Aβ and Tau markers. This study sustains the hypothesis that TSPO is mainly associated with microglia and in Aβ42-rich subdivisions in the hippocampus of non-demented elderly individuals.

Niemann-Pick Type C 1 (NPC1) and NPC2 Gene Variability in Demented Patients with Evidence of Brain Amyloid Deposition.

Variants in Niemann-Pick Type C genes (NPC1 and NPC2) have been suggested to play a role as risk or disease modifying factors for Alzheimer's disease (AD). The aim of this study was to analyze NPC1 and NPC2 variability in demented patients with evidence of brain amyloid-β 1-42 (Aβ) deposition and to correlate genetic data with clinical phenotypes. A targeted Next Generation Sequencing panel was customized to screen NPC1, NPC2, and main genes related to neurodegenerative dementias in a cohort of 136 demented patients with cerebrospinal fluid (CSF) low Aβ levels or positive PET with Aβ tracer and 200 non-demented geriatric subjects. Seven patients were carriers of NPC variants in heterozygosis. Four of them displayed pathogenic variants previously found in NPC patients and one AD patient had a novel variant. The latter was absent in 200 non-demented elderly subjects. Five of seven patients (70%) exhibited psychiatric symptoms at onset or later as compared with 43%in non-carriers (p > 0.05). The frequency of NPC1 and NPC2 heterozygous variants in patients with CSF evidence of Aβ deposition is higher than in the general population.

Dynamic Functional Connectivity Signifies the Joint Impact of Dance Intervention and Cognitive Reserve.

Research on dance interventions (DIs) in the elderly has shown promising benefits to physical and cognitive outcomes. The effect of DIs on resting-state functional connectivity (rs-FC) varies, which is possibly due to individual variability. In this study, we assessed the moderation effects of residual cognitive reserve (CR) on DI-induced changes in dynamic rs-FC and their association on cognitive outcomes. Dynamic rs-FC (rs-dFC) and cognitive functions were evaluated in non-demented elderly subjects before and after a 6-month DI (n = 36) and a control group, referred to as the life-as-usual (LAU) group (n = 32). Using linear mixed models and moderation, we examined the interaction effect of DIs and CR on changes in the dwell time and coverage of rs-dFC. Cognitive reserve was calculated as the residual difference between the observed memory performance and the performance predicted by brain state. Partial correlations accounting for CR evaluated the unique association between changes in rs-dFC and cognition in the DI group. In subjects with lower residual CR, we observed DI-induced increases in dwell time [t(58) = –2.14, p = 0.036] and coverage [t(58) = –2.22, p = 0.030] of a rs-dFC state, which was implicated in bottom-up information processing. Increased dwell time was also correlated with a DI-induced improvement in Symbol Search (r = 0.42, p = 0.02). In subjects with higher residual CR, we observed a DI-induced increase in coverage [t(58) = 2.11, p = 0.039] of another rs-dFC state, which was implicated in top-down information processing. The study showed that DIs have a differential and behaviorally relevant effect on dynamic rs-dFC, but these benefits depend on the current CR level.

Sex-Related Differences in Regional Blood-Brain Barrier Integrity in Non-Demented Elderly Subjects.

The role of the blood–brain barrier (BBB) breakdown has been recognized as being important in Alzheimer’s disease pathogenesis. We aimed to evaluate whether regional BBB integrity differed according to sex and whether differences in BBB integrity changed as a consequence of aging or cognitive decline, using dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI). In total, 75 participants with normal cognition (NC) or mild cognitive impairment (MCI) underwent cognitive assessments and MRI examination including DCE-MRI. Regional Ktrans was calculated in cortical regions and the Patlak permeability model was used to calculate BBB permeability (Ktrans, min−1). Females had a lower median Ktrans in the cingulate and occipital cortices. In the “older old” group, sex differences in Ktrans were only observed in the occipital cortex. In the MCI group, sex differences in Ktrans were only observed in the occipital cortex. Age was the only predictor of cognitive assessment scores in the male MCI group; however, educational years and Ktrans in the occipital cortex could predict cognitive scores in the female MCI group. Our study revealed that females may have better BBB integrity in cingulate and occipital cortices. We also found that sex-related differences in BBB integrity are attenuated with aging or cognitive decline.

Moderate Mocha Coffee Consumption Is Associated with Higher Cognitive and Mood Status in a Non-Demented Elderly Population with Subcortical Ischemic Vascular Disease.

To date, interest in the role of coffee intake in the occurrence and course of age-related neurological and neuropsychiatric disorders has provided an inconclusive effect. Moreover, no study has evaluated mocha coffee consumption in subjects with mild vascular cognitive impairment and late-onset depression. We assessed the association between different quantities of mocha coffee intake over the last year and cognitive and mood performance in a homogeneous sample of 300 non-demented elderly Italian subjects with subcortical ischemic vascular disease. Mini Mental State Examination (MMSE), Stroop Colour-Word Interference Test (Stroop T), 17-items Hamilton Depression Rating Scalfe (HDRS), Activities of Daily Living (ADL), and Instrumental ADL were the outcome measures. MMSE, HDRS, and Stroop T were independently and significantly associated with coffee consumption, i.e., better scores with increasing intake. At the post-hoc analyses, it was found that the group with a moderate intake (two cups/day) had similar values compared to the heavy drinkers (≥three cups/day), with the exception of MMSE. Daily mocha coffee intake was associated with higher cognitive and mood status, with a significant dose-response association even with moderate consumption. This might have translational implications for the identification of modifiable factors for vascular dementia and geriatric depression.

Salivary cortisol and five-year change in cognitive performance in non-demented elderly subjects: a population-based study

Elevated cortisol levels have been associated with poorer cognitive performance in cross-sectional studies; this may be both a factor contributing to neurodegeneration and cognitive decline and a result of developing brain pathologies. However, it is still unclear (1) whether cortisol measures predict later cognitive decline and (2) whether cortisol changes over the years might be associated with cognitive changes. We analyzed data from CoLaus/PsyCoLaus, a prospective population-based study. Salivary cortisol (4 different measures on 1 day) and neuropsychological assessments were performed at a first visit and a follow-up visit 5 years later in 625 dementia-free participants aged ≥65 years. Salivary cortisol levels at waking and 30 minutes after waking, as well as longitudinal changes in cortisol 30 minutes after waking, cortisol awakening response, and cortisol AM-PM difference were associated with decline in global cognition. After controlling for potential confounders, only longitudinal changes in cortisol 30 minutes after waking remained associated with cognitive decline. These mostly negative findings indicate absent or subtle association between salivary cortisol and cognitive decline.

Multidomain intervention and/or omega-3 in nondemented elderly subjects according to amyloid status

IntroductionThe Multidomain Alzheimer Preventive Trial (MAPT) assessed the efficacy of omega-3 fatty acid supplementation, a multidomain intervention (MI), or a combination of both on cognition. Impact according to cerebral amyloid status was evaluated by PET scan. MethodsParticipants were nondemented and had memory complaints, limitation in one instrumental activity of daily living, or slow gait. The primary outcome was a change from baseline in 36 months measured with a cognitive composite Z score. ResultsNo effect was observed on cognition in the negative amyloid group (n = 167). In the positive amyloid group (n = 102), we observed a difference of 0.708 and 0.471 in the cognitive composite score between the MI plus omega-3 fatty acid group, the MI alone group, and the placebo group, respectively. DiscussionMI alone or in combination with omega-3 fatty acids was associated with improved primary cognitive outcome in subjects with positive amyloid status. Trial RegistrationClinicalTrials.gov Identifier: NCT01513252.

Decreased Function of Delayed Recall in Non-demented Elderly Subjects With Apolipoprotein E ε4 Allele.

Apolipoprotein E (APOE) is the major genetic risk factor for late-onset Alzheimer’s disease (AD). Inconsistent results about the role of APOE ε4 alleles on cognitive decline of community non-dementia elderly have been reported. This study aimed to examine the relationship between APOE ε4 allele and cognitive abilities in the subjects aged 60 years or above from a community in Shanghai, China. A total of 1445 participants voluntarily accepted the analysis of APOE genotype and global cognitive assay using the Mini Mental Status Evaluation (MMSE). There were no significant differences in total MMSE scores between APOE ε4 carriers and non-carriers. In addition, the performances of orientation, registration, attention, calculation, and language had no significant differences between subjects with and without APOE ε4 allele. However, stratified analysis showed that the performance of delayed recall in subjects with APOE ε4 allele was inferior to that in non-ε4 carriers (p = 0.041). Further, the multiple linear regression analysis showed the significant correlations between the presence of APOE ε4 allele and the scores of the delayed memory subdomain if age, gender, and education were adjusted but no significant correlations if the related factors were not adjusted. The results indicate that significant impact of APOE ε4 allele only on the delay memory but not on global or other sub-domains of cognitive abilities.

The Role of MRI Biomarkers and Their Interactions with Cognitive Status and APOE ε4 in Nondemented Elderly Subjects

Purpose: (1) To investigate atrophy patterns of hippocampal subfield volume and Alzheimer’s disease (AD)-signature cortical thickness in mild cognitive impairment (MCI) patients; (2) to explore the association between the neuropsychological (NP) and the brain structure in the MCI and older normal cognition group; (3) to determine whether these associations were modified by the apolipoprotein E (APOE) ε4 gene and cognitive status. Methods: The FreeSurfer software was used for automated segmentation of hippocampal subfields and AD-signature cortical thickness for 22 MCI patients and 23 cognitive normal controls (NC). The volume, cortical thickness, and the neuropsychological scale were compared with two-sample t tests. Linear regression models were used to determine the association between the NP and the brain structure. Results: Compared with the NC group, MCI patients showed a decreased volume of the left presubiculum, subiculum and right CA2_3 and CA4_DG (p < 0.05, FDR corrected). The volume of these regions was positively correlated with NP scores. Of note, these associations depended on the cognitive status but not on the APOE ε4 status. The left subiculum and presubiculum volume were positively correlated with the Montreal Cognitive Assessment (MoCA) scores only in the MCI patients. Conclusion: Atrophy of the hippocampal subfields may be a powerful biomarker for MCI in the Chinese population.

Basal forebrain cholinergic system volume is associated with general cognitive ability in the elderly

ObjectiveAt the present, it is unclear whether association of basal forebrain cholinergic system (BFCS) volume with cognitive performance exists in healthy as well as in cognitively impaired elderly subjects. Whereas one small study reported an association of BFCS volume with general cognitive ability ‘g’ in healthy ageing, effects on specific cognitive domains have only been found in subjects with cognitive decline. Here we aim to clarify whether an association of BFCS volume and ‘g’ is present in a larger sample of elderly subjects without obvious symptoms of dementia and whether similar associations can also be observed in specific cognitive domains. Methods282 pre-surgical patients from the BioCog study (aged 72.7 ± 4.9 years with a range of 65–87 years, 110 women) with a median MMSE score of 29 points (range 24–30) were investigated. BFCS and brain volume as well as brain parenchymal fraction were assessed in T1-weighted MR images using SPM12 and a probabilistic map of the BFCS. Neuropsychological assessment comprised the CANTAB cognitive battery and paper-and-pencil based tests. For data analysis, generalised linear models and quantile regression were applied. ResultsSignificant associations of BFCS volume with ‘g’ and several cognitive domains were found, with the strongest association found for ‘g’. BFCS volume explained less variance in cognitive performance than brain volume. The association was not confounded by brain parenchymal fraction. Furthermore, the association of BFCS volume and ‘g’ was similar in high- and low-performers. ConclusionOur results extend previous study findings on BFCS volume associations with cognition in elderly subjects. Despite the observed associations of BFCS volume and cognitive performance, this association seems to reflect a more general association of brain volume and cognition. Accordingly, a specific association of BFCS volume and cognition in non-demented elderly subjects is questionable.

White matter asymmetries in patients with cerebral small vessel disease.

White matter asymmetries of the human brain have been well documented using diffusion tensor imaging. The purpose of this study was to investigate white matter asymmetry across the whole brain in cerebral small vessel disease patients and evaluate the relation between the factors which often represent disease existence and white matter asymmetry. A total of 105 nondemented elderly subjects with cerebral small vessel disease aged between 60 and 85 years were included in this study. All subjects underwent T1 MPRAGE, fluid-attenuated inversion recovery, and diffusion tensor imaging scanning. With tract-based spatial statistics in diffusion tensor imaging, this study examined the white matter asymmetries and the correlations between white matter asymmetries and four distinct factors such as deep white matter hyperintensities score, periventricular hyperintensities score, cerebral microbleed number and lacune number. The study suggested the asymmetric microstructural change in small vessel disease patients involving the right side being more injured than the left. The four factors jointly affect right brain anisotropy decrease in the middle cerebellar peduncle, the cerebral peduncle, the pontine crossing tract, the corticospinal tract, the medial lemniscus, the posterior limb of internal capsule, and the frontal pattern of white matter. Results of the study demonstrated the lost right white matter may be the main origin of dysfunction in small vessel disease patients. This asymmetry should help with the evaluation of prognostic indicators of disease progression in lesion-based neuropathology..

Triglycerides are negatively correlated with cognitive function in nondemented aging adults.

Vascular risk factors like hyperlipidemia may adversely affect brain function. We hypothesized that increased serum triglycerides are associated with decreased executive function and memory in nondemented elderly subjects. We also researched possible vascular mediators and white matter microstructure as assessed with diffusion tensor imaging (DTI). Participants were 251 nondemented elderly adults (54% male) with a mean age of 78 (SD = 6.4; range: 62-94) years and a mean education of 15.6 (SD = 2.9; range: 8-23) years. Fasting blood samples were used to detect serum triglyceride and low-density lipoprotein (LDL) levels along with ApoE4 status. DTI was used to determine whole brain fractional anisotropy (FA). Composite executive and memory scores were derived from item response theory. Clinical Dementia Rating (CDR) scores provided informant-based measures of daily functioning. Triglyceride levels were inversely correlated with executive function, but there was no relationship with memory. Controlling for age, gender, and education did not affect this correlation. This relationship persisted after controlling for vascular risk factors like LDL, total cholesterol, CDR and ApoE4 status. Lastly, adding whole-brain FA to the model did not affect the correlation between triglycerides and executive function. Triglyceride levels are inversely correlated with executive function in nondemented elderly adults after controlling for age, education, gender, total cholesterol, LDL, ApoE4 status, CDR, and white-matter microstructure. The fact that the effect of triglycerides on cognition was not clearly mediated by vascular risks or cerebrovascular injury raises questions about widely held assumptions of how triglycerides might impact cognition function. (PsycINFO Database Record

REGIONAL AMYLOID DEPOSITS DO NOT IMPAIR NEURONAL FUNCTION IN A COGNITION-RELEVANT MANNER

The mechanisms that link amyloid-β pathology to the neuronal impairments that underlie cognitive deficits in Alzheimer's Disease (AD) are a matter of ongoing debate. A recent molecular imaging study indicated that regional amyloid deposits do not generally link to glucose hypometabolism of the affected brain region, arguing against a local neurotoxic effect of accumulated amyloid-β protein. However, accumulated amyloid may also result in functional derangements that are not associated with decreased glucose utilization, such as dysfunctional neuronal hyperactivity. We aimed to study the functional consequences of regional amyloid accumulation by using sensitive performance measures in domain-specific neuropsychologic tests as markers of regional brain dysfunction. We investigated associations of regional amyloid deposits in cognition-specific functional brain networks with impairments in the respective cognitive processes using amyloid-sensitive AV45-PET and neuropsychologic test data of 577 nondemented elderly subjects (cognitively normal and MCI) participating in the ADNI study. Specifically, we used partial correlation analyses controlled for age, sex, education, and diagnosis to examine amyloid-cognition associations within “posterior medial” (PM) and “anterior temporal” (AT) brain networks known to specifically subserve episodic (30-min delayed recall, DR) and semantic memory (Boston Naming Test, BNT) processes, respectively. The regional specificity of the associations was assessed by additional control for global cortical amyloid load. For comparison, analogous analyses assessed network-specific cognition correlates of regional glucose hypometabolism measured by FDG-PET. Amyloid load in the PM network correlated with worse DR (r=-0.17, p<0.001), but not with worse BNT performance. Amyloid load in the AT network correlated with worse BNT (r=-0.13, p=0.001) performance, but even more so with worse DR (r=-0.22, p<0.001). Moreover, after controlling for global cortical amyloid burden, none of the regional associations remained significant. By contrast, globally controlled glucose hypometabolism correlated with cognitive dysfunction in a network-specific manner, correlating with DR in the PM (p<0.001) and with BNT in the AT (p<0.001), but not vice versa (both p>0.05). In contrast to FDG-PET measured hypometabolism, network-specific amyloid load does not specifically associate with dysfunction in the respective cognitive domain, corroborating recent evidence of negligible local neurotoxicity of accumulated amyloid-β protein.

AMYLOID DEPOSITION AND BRAIN STRUCTURE AS LONG-TERM PREDICTORS OF DEMENTIA IN COGNITIVELY NORMAL AND MCI INDIVIDUALS

Structural MRI and amyloid PET scans have been used as short-term, but not long-term predictors of incident dementia in elderly individuals. The purpose of this study is to examine the long-term association between MRI brain structural integrity and PET measures of amyloid-β (Aβ) deposition, and incident dementia 183 non-demented elderly subjects (mean age 85.5) were followed from 2009 to 2015 with annual clinical evaluation (mean follow up 5.2 years). Pittsburgh compound-B (PiB) PET was analyzed as a dichotomous and continuous variable. Neurodegeneration was based on hippocampal (HIP) volumes (<25th percentile), and small vessel disease on white matter hyperintensities (WMH) (>75thpercentile). In 2009, 148 participants were categorized as cognitively normal (CN) and 35 as mild cognitive impairment (MCI). By 2015, 25% of the CN participants and 66% of MCI developed dementia during follow-up. Risk of dementia was linearly related to amyloid deposition. Dementia incidence was 32/1000 age adjusted person-years (PYs) in participants with a PiB SUVR <1.34, and 97/1000 in subjects with PiB SUVR >2.16. HIP and WMH were also associated with increased risk of dementia. In combined models, the CN who had normal PiB, HIP and WMH had very low risk of dementia (35/1000 PYs). By contrast, when all three biomarkers were abnormal, the risk was 192.3/1000 PYs. PiB-positivity in isolation (SUVR >1.57) was not associated with an increased risk of dementia among CN (37/1000 PYs), nor was HIP atrophy (40.6/1000 PYs) or WMH volume alone (20/1000 PYs). However, using continuous variables, greater amyloid deposition (HR: 2.62), smaller HIP (HR: 0.69), and more WMH (HR: 3.37) independently increased the risk of incident dementia. We found that when the dichotomous measures of the common biomarkers for Alzheimer's disease (AD) are considered in isolation, they are unrelated to clinical dementia risk. It is only when all three abnormalities are present, and the AD pathology is established, and the clinical symptoms of dementia are imminent.

Personality, Cortisol, and Cognition in Non-demented Elderly Subjects: Results from a Population-Based Study.

Certain personality traits, in particular higher neuroticism, have been associated, on one hand, with elevated cortisol levels, and on the other hand, with poorer cognitive performance. At the same time, several studies highlighted the association between high cortisol and poor cognitive functioning. Here, we hypothesized that increased cortisol may be associated with poorer cognition and with certain personality traits (mainly high neuroticism), and that personality might explain the association between cortisol and cognition. A cross-sectional analysis was conducted using data from Colaus/PsyColaus, a population-based study involving residents of Lausanne, Switzerland. Salivary cortisol samples (upon waking, 30 min after waking, at 11 am and at 8 pm) along with cognitive and personality measures were obtained from 643 non-demented participants aged at least 65. Personality traits were assessed using the NEO Five-Factor Inventory (NEO-FFI). We examined the links between the cortisol Area under the Curve (AUC), the Clinical Dementia Rating Sum of Boxes (CDRSOB) and the NEO-FFI scores. No association was found between personality traits and the CDRSOB or the MMSE score, controlling for age, sex, depression, education and BMI. However, the executive functioning domain z-score was negatively associated with agreeableness (p = 0.005; slope = -0.107 [-0.181; -0.033]) and openness (p = 0.029; slope = -0.081 [-0.154; -0.008]) after controlling for age, sex, depression, education and BMI. The CDRSOB score was positively associated with the cortisol AUC after controlling for age, sex, BMI, education and depression, (p = 0.003; slope = 0.686 [0.240; 1.333]). This association remained significant after controlling for personality traits and for the interaction between personality traits and the cortisol AUC (p = 0.006; slope = 0.792 [0.233; 1.352]. High agreeableness and openness might be associated with poorer executive performance in later life. Increased cortisol may be associated with both specific personality traits (high extraversion, low openness) and worse cognitive performance. Increased salivary cortisol does not mediate the relationship between personality traits and cognitive impairment.

Chronic Kidney Disease and Subclinical Brain Infarction Increase the Risk of Vascular Cognitive Impairment: The Sefuri Study

The purpose of this study was to determine the complex associations among chronic kidney disease (CKD), subclinical brain infarction (SBI), and cognitive impairment. We used structural equation modeling (SEM) to examine the complex relationships among CKD, SBI, and cognitive function with Mini-Mental State Examination (MMSE; global function) and modified Stroop test (executive function) in a population-based cohort of 560 non-demented elderly subjects. Path analysis based on SEM revealed that the direct paths from estimated glomerular filtration rate (eGFR) to SBI and from SBI to executive function were significant (β = -.10, P = .027, and β = .16, P < .001, respectively). Furthermore, the direct path from eGFR to executive function was also significant (β = -.12, P = .006), indicating that the effects of CKD on executive function are independent of SBI. The direct paths from age and education to global cognitive function were highly significant (β = -.17 and .22, respectively, P < .001), whereas the direct path from eGFR to MMSE was not significant. Our findings indicate that CKD confers a risk of vascular cognitive impairment or executive dysfunction through mechanisms dependent and independent of SBI. Treating CKD may be a potential strategy to protect against vascular cognitive impairment or executive dysfunction in healthy elderly subjects.

Effect of a ketogenic meal on cognitive function in elderly adults: potential for cognitive enhancement.

Glucose is the principal energy substrate for the brain, although ketone bodies are an effective alternative. Evidence suggests that elevation of plasma ketone body levels through oral intake of medium chain triglycerides (MCTs) may improve cognitive function. We tried to examine the possible effects of a ketogenic meal serving on cognition in elderly non-demented subjects. Subjects were 19 non-demented elderly adults over 60years old (13 females; mean age: 66.1±2.9years) who underwent neurocognitive tests 90 and 180min after oral intake of a ketogenic meal (Ketonformula®) containing 20g of MCTs and an isocaloric placebo meal without MCTs on separate days. Elevation of plasma ketone concentration after intake of a single ketogenic meal containing 20g of MCTs was confirmed (all p<0.001). As for cognition, improvements were observed in the digit span test, Trail-Making Test B, and the global score (Z=-2.4, p=0.017) following the ketogenic meal and the change in the executive functioning score was positively correlated with that of the plasma β-hydroxybutyrate level. The cognition-enhancing effect was observed predominantly for individuals who had a relatively low global score at baseline (Z=-2.8, p=0.005), compared to individuals with a high global score (Z=-0.7, p=0.51). Plasma levels of ketone bodies were successfully increased after intake of the ketogenic meal. The ketogenic meal was suggested to have positive effects on working memory, visual attention, and task switching in non-demented elderly.

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.

Abstract TP453: Physical Inactivity Associated With Vascular Depression or Apathy Leads to Hippocampal Atrophy and Memory Dysfunction in Community-dwelling Elderly Subjects: The Sefuri Study

Background and Purpose: Vascular depression has negative effects on physical activity, which is a robust preventive factor against Alzheimer's disease or hippocampal atrophy. Therefore, we investigated the relationship among vascular depression (i.e., apathy associated with deep white matter lesions [DWMLs]), physical activity, hippocampal atrophy, and memory function using structural equation modeling (SEM). Subjects and Methods: We examined 213 non-demented elderly subjects without clinically apparent depression. All participants underwent Mini-Mental State Examination, Rivermead Behavioral Memory Test [RBMT] for episodic long-term memory, and a visual analogue version of the Starkstein’s apathy scale (Yao et al., Hypertens Res 2009;32:586). Physical activities were assessed with a questionnaire consisted of 3 components: leisure-time, work, and sport activities (Baecke et al., Am J Clin Nutr 1982;36:936). We evaluated the degree of hippocampal atrophy, using a software program the voxel-based specific regional analysis system for Alzheimer’s disease (VSRAD advance) based on SPM8 plus DARTEL (Diffeomorphic Anatomical Registration Through an Exponentiated Lie algebra). Results: When possible confounders were entered into the logistic regression model, the independent predictors of hippocampal atrophy (the highest quintile of VSRAD z-score) were age (OR per 10 years 3.257, 95%CI 1.988-5.338), and leisure-time physical activity (OR per 1-point 0.810, 95%CI 0.707-0.928). Path analysis based on SEM indicated that the direct paths from DWMLs to apathy (β= -0.18, p&lt;0.01) and from apathy to leisure-time activity (β= 0.23, p&lt;0.001) were significant. Furthermore, the direct paths from leisure-time activity to hippocampal atrophy (β= -0.18, p&lt;0.01) and from hippocampal atrophy to memory dysfunction (RBMT) (β= -0.26, p&lt;0.001) were significant. The presented model reasonably fit the data: goodness of fit index = 0.97, adjusted goodness of fit index = 0.93, comparative fit index = 0.97, and root mean square error of approximation = 0.04. Conclusions: Based on the present SEM analysis, we propose a hypothesis that physical inactivity associated with vascular depression would lead to hippocampal atrophy or Alzheimer’s disease.