Non-demented Elderly Individuals Research Articles

Differences in resting-state brain networks and gray matter between APOE ε2 and APOE ε4 carriers in non-dementia elderly.

Apolipoprotein E (APOE) ε2 and APOE ε4 are the most distinct alleles among the three APOE alleles, both structurally and functionally. However, differences in cognition, brain function, and brain structure between the two alleles have not been comprehensively reported in the literature, especially in non-demented elderly individuals. A neuropsychological test battery was used to evaluate the differences in cognitive performance in five cognitive domains. Independent component analysis (ICA) and voxel-based morphometry (VBM) were used separately to analyze resting-state functional magnetic resonance imaging (rs-fMRI) data and the structure MRI data between the two groups. Finally, correlations between differential brain regions and neuropsychological tests were calculated. APOE ε2 carriers had better cognitive performance in general cognitive, memory, attention, and executive function than APOE ε4 carriers (all p < 0.05). In ICA analyses of rs-fMRI data, the difference in the resting-state functional connectivity (rsFC) between two groups is shown in 7 brain networks. In addition, VBM analyses of the T1-weighted image revealed that APOE ε2 carriers had a larger thalamus and right postcentral gyrus volume and a smaller bilateral putamen volume than APOE ε4 carriers. Finally, differences in brain function and structure may be might be the reason that APOE ε2 carriers are better than APOE ε4 carriers in cognitive performance. These findings suggest that there are significant differences in brain function and structure between APOE ε2 carriers and APOE ε4 carriers, and these significant differences are closely related to their cognitive performance.

The platelet transcriptome and proteome in Alzheimer's disease and aging: an exploratory cross-sectional study.

Introduction: Alzheimer's disease (AD) and aging are associated with platelet hyperactivity. However, the mechanisms underlying abnormal platelet function in AD and aging are yet poorly understood. Methods: To explore the molecular profile of AD and aged platelets, we investigated platelet activation (i.e., CD62P expression), proteome and transcriptome in AD patients, non-demented elderly, and young individuals as controls. Results: AD, aged and young individuals showed similar levels of platelet activation based on CD62P expression. However, AD and aged individuals had a proteomic signature suggestive of increased platelet activation compared with young controls. Transcriptomic profiling suggested the dysregulation of proteolytic machinery involved in regulating platelet function, particularly the ubiquitin-proteasome system in AD and autophagy in aging. The functional implication of these transcriptomic alterations remains unclear and requires further investigation. Discussion: Our data strengthen the evidence of enhanced platelet activation in aging and provide a first glimpse of the platelet transcriptomic changes occurring in AD.

APOE ε4 status and plasma p-tau181 interact to influence cognitive performance among non-demented older adults

ObjectiveIn this study, we aimed to investigate the relationships among plasma p-tau181, APOE ε4, and cognitive performance in non-demented elderly individuals. MethodsWe used individuals (n = 630) with cognitive normal (CN, n = 182) and mild cognitive impairment (MCI, n = 448). Multiple linear regression models were performed to test the effects of APOE ε4 × plasma p-tau181 interaction on MMSE, CDR-SOB, ADAS-cog13, and RAVLT immediate recall. All models adjusted for age, sex, and education. ResultsIn total, our study comprised 630 samples including 364 APOE ε4 non-carriers and 266 APOE ε4 carriers. In APOE ε4 carriers, plasma p-tau181 was significantly associated with MMSE (B = −0.04, p = 0.003), ADAS-Cog13 (B [unstandardized coefficient] = 0.21, p < 0.001), CDR-SB (B = 0.02, p = 0.003) and RAVLT immediate recall ((B = −0.17, p = 0.035). After correcting for Aβ status and diagnosis, the interaction between APOE ε4 and plasma p-tau181 was significant or marginally significant associations for RAVLT immediate recall (p = 0.076), MMSE (p = 0.011), CDR (p = 0.008), and ADAS-Cog13 (p < 0.001). ConclusionsOur findings suggested that plasma p-tau181 levels predicted cognitive performance among non-demented older adults, but only in the APOE ε4 carriers.

Metformin use and brain atrophy in nondemented elderly individuals with diabetes.

There is a shred of growing evidence demonstrating that diabetic patients are at higher risk of developing Alzheimer's disease compared to the general population. The previous investigation showed the protective effect of metformin for delaying dementia in diabetic patients. However, there are limited data on the effect of metformin on structural changes. This study aims to investigate the effect of metformin on hippocampal and cortical volumes in non-demented diabetic individuals. We entered 157 non-demented diabetic subjects including 89 mild cognitive impairment (MCI), and 68 cognitively healthy individuals from Alzheimer's disease Neuroimaging Initiative (ADNI) which were then categorized as metformin users and non-users. We used the ANCOVA model for measuring the association between metformin use and hippocampal and cortical volumes. Among 157 subjects with a mean age of 71.8 (±7.7) included in this study, 76 individuals were stratified as metformin users. Results of the univariate model indicate that metformin users had a higher right (p=0.003) and left parietal lobe volume (p=0.004). Moreover, the volume of left cingulate was higher in those who used metformin compared to those not used it (p=0.027). Our results were also significant for the right frontal lobe and indicated that metformin users had higher volume (p=0.035). There were no significant differences in the hippocampus, occipital, and temporal regions. Our findings showed the protective effects of metformin on brain volumes in non-demented elderly individuals with diabetes. Comparing the groups show strong enough results regarding the lower atrophy in metformin users.

Relationship between neuropsychological test scores and hippocampal atrophy in non-demented Japanese older adults

BackgroundIt is essential to detect morphological changes in the brain prior to the onset of cognitive decline. Although hippocampal volumes have been reported to be correlated with scores on neuropsychological tests, this relationship is still unclear among Japanese non-demented older adults. Thus, this exploratory retrospective study aimed to identify neuropsychological tests that correlate with the degree of hippocampal atrophy in Japanese non-demented older adults. MethodsThirteen non-demented Japanese older adults aged 71.2 ± 5.2 years were included. Hippocampal atrophy was evaluated by assessing the participants’ MRI scans using the voxel-based specific regional analysis system for Alzheimer’s disease (VSRAD) software. Spearman’s partial correlation analyses were conducted to reveal relationships between VSRAD scores and neuropsychological test scores, including Raven’s Colored Progressive Matrices test (RCPM), the Standard Verbal Paired Associate Learning test (SP-A), and the Trail Making Test (TMT) scores by controlling for age, sex, and years of education. ResultsThe Spearman’s partial correlation analysis results revealed that there were significant correlations between the degree of hippocampal atrophy and RCPM (rho = -0.691, p = 0.027), TMT part B (rho = 0.823, p = 0.003), and the related SP-A test scores (rho = -0.663, p = 0.027). ConclusionsOur results indicate that neuropsychological tests, particularly the TMT part B, might be used in assessing the degree of hippocampal atrophy in non-demented Japanese elderly individuals and should be studied further in the future to develop screening methods to detect brain atrophy.

Low Subicular Volume as an Indicator of Dementia-Risk Susceptibility in Old Age

IntroductionHippocampal atrophy is an established Alzheimer’s Disease (AD) biomarker. Volume loss in specific subregions as measurable with ultra-high field magnetic resonance imaging (MRI) may reflect earliest pathological alterations.MethodsData from positron emission tomography (PET) for estimation of cortical amyloid β (Aβ) and high-resolution 7 Tesla T1 MRI for assessment of hippocampal subfield volumes were analyzed in 61 non-demented elderly individuals who were divided into risk-categories as defined by high levels of cortical Aβ and low performance in standardized episodic memory tasks.ResultsHigh cortical Aβ and low episodic memory interactively predicted subicular volume [F(3,57) = 5.90, p = 0.018]. The combination of high cortical Aβ and low episodic memory was associated with significantly lower subicular volumes, when compared to participants with high episodic memory (p = 0.004).DiscussionOur results suggest that low subicular volume is linked to established indicators of AD risk, such as increased cortical Aβ and low episodic memory. Our data support subicular volume as a marker of dementia-risk susceptibility in old-aged non-demented persons.

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.

Visit-to-visit blood pressure variability in mild cognitive impairment: A possible marker of Alzheimer's disease in the SPRINT study?

Visit-to-visit blood pressure variability in mild cognitive impairment: A possible marker of Alzheimer's disease in the SPRINT study?

Structural differences in amyloid-β fibrils from brains of nondemented elderly individuals and Alzheimer's disease patients

Although amyloid plaques composed of fibrillar amyloid-β (Aβ) assemblies are a diagnostic hallmark of Alzheimer's disease (AD), quantities of amyloid similar to those in AD patients are observed in brain tissue of some nondemented elderly individuals. The relationship between amyloid deposition and neurodegeneration in AD has, therefore, been unclear. Here, we use solid-state NMR to investigate whether molecular structures of Aβ fibrils from brain tissue of nondemented elderly individuals with high amyloid loads differ from structures of Aβ fibrils from AD tissue. Two-dimensional solid-state NMR spectra of isotopically labeled Aβ fibrils, prepared by seeded growth from frontal lobe tissue extracts, are similar in the two cases but with statistically significant differences in intensity distributions of cross-peak signals. Differences in solid-state NMR data are greater for 42-residue amyloid-β (Aβ42) fibrils than for 40-residue amyloid-β (Aβ40) fibrils. These data suggest that similar sets of fibril polymorphs develop in nondemented elderly individuals and AD patients but with different relative populations on average.

The relationship between plasma free fatty acids, cognitive function and structural integrity of the brain in middle-aged healthy humans

Background: The cerebral composition of ω-3 and ω-6 polyunsaturated fatty acids (PUFAs) is believed to influence cognitive function and structural damage of the aging brain. However, existing data is inconsistent.Materials and Methods: This retrospective study explored the association between free plasma PUFA concentrations, cognitive function and brain structure atrophy in a well-characterized community-dwelling cohort of elderly individuals without stroke and dementia. Ten different fatty acids were analyzed in stored plasma samples from 391 non-demented elderly individuals by gas chromatography mass spectrometry. Neuropsychiatric tests capturing memory, executive function and visuopractical skills were performed in all participants. Brain atrophy was assessed by MRI in a subset of 167 individuals.Results: Higher plasma concentrations of free ω-6 PUFAs (p = 0.042), and, in particular, linoleic acid (p = 0.01), were significantly associated with lower executive function. No significant association existed between ω-3 PUFA concentrations and cognitive functioning. The volume of the frontal lobes was inversely associated with ω-6 PUFAs, whereas ω-3 PUFAs were positively related with temporal lobe volumes. All associations did not withstand correction for multiple comparisons.Conclusions: Our study suggests subtle effects of PUFA imbalances on cognition and brain structure. Yet the observed associations are weak and unlikely to be of clinical relevance. The brain regions that seem to be most sensitive to imbalances of ω-3 and ω-6 PUFAs are the frontal and temporal lobes.

Cognitive and brain cytokine profile of non-demented individuals with cerebral amyloid-beta deposition

BackgroundBrain inflammation has been increasingly associated with early amyloid accumulation in Alzheimer’s disease models; however, evidence of its occurrence in humans remains scarce. To elucidate whether amyloid deposition is associated with neuroinflammation and cognitive deficits, we studied brain inflammatory cytokine expression and cognitive decline in non-demented elderly individuals with and without cerebral amyloid-beta deposition.MethodsGlobal cognition, episodic, working, and semantic memory, perceptual speed, visuospatial ability, and longitudinal decline (5.7 ± 3.6 years) in each cognitive domain were compared between elderly individuals (66–79 years) with and without cerebral amyloid-beta deposition. The expression of 20 inflammatory cytokines was analyzed in frozen temporal, parietal, and frontal cortices and compared between older individuals with and without amyloid-beta deposition in each brain region. Correlation analyses were performed to analyze associations between amyloid-beta load, cytokine expression, and cognitive decline.ResultsIndividuals with cortical amyloid-beta deposition displayed deficits and a faster rate of cognitive decline in perceptual speed as compared with those individuals without amyloid-beta. This decline was positively associated with cortical amyloid-beta levels. Elderly individuals with amyloid-beta deposition had higher levels of IL-1β, IL-6, and eotaxin-3 in the temporal cortex accompanied by an increase in MCP-1 and IL-1β in the parietal cortex and a trend towards higher levels of IL-1β and MCP-1 in the frontal cortex as compared with age-matched amyloid-free individuals. Brain IL-1β levels displayed a positive association with cortical amyloid burden in each brain region. Finally, differential cytokine expression in each cortical region was associated with cognitive decline.ConclusionsElderly individuals with amyloid-beta neuropathology but no symptomatic manifestation of dementia, exhibit cognitive decline and increased brain cytokine expression. Such observations suggest that increased cytokine expression might be an early event in the Alzheimer’s continuum.

Apathy and executive functioning among non-demented community-dwelling elderly individuals in an everyday environment: the mediating effect of impulsivity.

Apathy is common in normal ageing and widely recognized as a predictor of cognitive decline, especially in executive functions. Much less characterized than apathy in the elderly is impulsivity, which increases with ageing. It is also frequently described in comorbidity with apathy in various clinical populations, in whom it is associated with poorer executive functioning. In the present study, by capitalizing on a multidimensional approach, we explore the mediating role of facets of impulsivity on the bidirectional relationships between apathy dimensions and executive functioning in non-demented community-dwelling elderly individuals in daily life. A sample of non-demented community-dwelling older adults (n= 101) completed self-rated questionnaires. Apathy was measured by the Apathy Evaluation Scale; impulsivity was examined through the Urgency, Premeditation, Perseverance, Sensation Seeking, Positive Urgency (UPPS-P) Impulsive Behaviour Scale; and executive functioning in daily life was assessed by the Behaviour Rating Inventory of Executive Function-Adult (BRIEF-A). Two models positing mediation were tested using conditional process modelling. Hierarchical regressions controlling for depressive symptoms indicated that the cognitive apathy dimension was associated with the UPPS-P facets sensation seeking, lack of perseverance, and premeditation. Among the UPPS-P facets, lack of perseverance and negative urgency were found to contribute significantly to BRIEF-A Metacognitive index variance. Finally, in both models, lack of perseverance was found to totally mediate the relationship between cognitive apathy and the BRIEF-A Metacognitive index. These preliminary findings suggest that, in normal ageing, apathy may share an overlap with impulsivity, contradicting the notion they represent opposite ends of a single behavioural spectrum. Our results argue for bidirectional relationship between a specific apathy dimension (i.e. cognitive apathy) and executive functioning. Moreover, they shed new light on the underlying psychological process implicated (i.e. lack of perseverance) among older adults without dementia and represent an interesting prospect for psychological interventions.

Effects of smartphone application-based cognitive training at home on cognition in community-dwelling non-demented elderly individuals: A randomized controlled trial.

IntroductionWe investigated whether cognitive function improves in elderly individuals after Application‐based Cognitive Training at Home (ACTH) for 12 months.MethodsA total of 389 non‐demented elderly volunteers aged over 60 years were recruited and randomly assigned to the intervention or control group. The intervention group underwent daily ACTH (with regular feedback from the administrator) and monthly offline cognitive training in groups for 12 months. All participants received a computerized cognitive test battery called Inbrain Cognitive Screening Test (Inbrain‐CST) at baseline and 6 and 12 months. The primary outcome was the change in the total composite score of Inbrain‐CST, and secondary outcomes included changes in composite scores in five cognitive domains of Inbrain‐CST.ResultsThe intervention group outperformed the control group in terms of the total score (P = .001) and subscores of language (P < .001) and memory (P < .001) domains at 12 months.DiscussionACTH improved global cognition in community‐dwelling non‐demented elderly individuals.

Hippocampal volume loss is associated with PET amyloid deposition in nondemented elderly individuals

AbstractBackgroundAmyloid‐beta (Aβ) plaques are among the hallmark pathologies of Alzheimer’s disease (AD) and could potentially influence the aggregation of tau pathology, which is associated with neurodegeneration in AD. Prior work has demonstrated that left hippocampal atrophy is present in both Alzheimer’s disease (AD) and mild cognitive impairment (MCI). However, these relationships are not clear in preclinical AD (i.e. those with Aβ biomarkers but no clinical impairment). This study assesses the relationship between Aβ pathology and hippocampal volume in nondemented older adults without clinical impairment.MethodData from 54 adults (60‐85 years of age, 41 female) enrolled in the Biomarker Exploration for Aging, Cognition, and Neurodegeneration (BEACoN) study were included in this analysis. Participants underwent T1‐weighted MRI scans (MPRAGE) and PET amyloid scans with F18‐florbetapir (AV‐45) at the University of California, Irvine. Aβ status (+ or ‐) was determined by the composite score defined by Jack et al (Alz Dem 2017). Each subject’s T1 weighted MRI image was skull stripped and run through the joint label fusion (JLF) pipeline in ANTs to obtain medial temporal lobe subregion volumes and surface area. Cortical reconstruction was performed using Freesurfer 6.0 to obtain estimated total intracranial volume (ICV). All scans were then subjected to visual QC to ensure high quality segmentations. Of the sample of 54, 39 (29F) were Aβ‐ and 15 (12F) were Aβ+. We used two multiple regressions to determine if Aβ status was associated with left hippocampal volume. The first treated Aβ status as a binary variable and the second used the continuous SUVR measure in the AD composite region. Both models accounted for the effect of age and gender.ResultWe found a significant association between left hippocampal volume and Aβ status, which remained significant after adjusting for age and gender. The result was further corroborated by using the continuous SUVR measures.ConclusionOur results suggest that the association between amyloid deposition and hippocampal atrophy may begin years before the onset of Alzheimer’s disease and can be detected even in nondemented older adults. Future work is needed to examine whether these relationships change longitudinally.

Operationalization of the ATN classification scheme in preclinical AD: Findings from EPAD V500.0 data release

AbstractBackgroundThe goal of this study is to assess neuropsychological and radiological characteristics according to the ATN scheme in the EPAD Longitudinal Cohort Study (EPAD‐LCS) after establishing data‐driven cut‐offs for classification.MethodATN cut‐off values were determined in a deeply phenotyped cohort of 500 nondemented elderly individuals. Amyloid and p‐tau in the cerebrospinal fluid were quantified with Roche Elecsys assays. Hippocampal volume was calculated using LEAP pipeline. The intersection poin of two‐component Gaussian mixture models was used to establish cut‐off values for CSF amyloid ß42 (A) and p‐tau (T). Age‐adjusted w‐scores were used to establish a cut‐off value for neurodegeneration (N). Only subjects classified as healthy controls (A‐T‐N‐) or in the Alzheimer spectrum (A+T‐N‐, A+T+N, A+T+N+) were included. Multinomial regression was performed to test whether significant differences among the ATN groups could be detected with the EPAD Neuropsychological Examination (ENE) after correcting for age, sex, years of education, and site of data collection.ResultOut of the initial sample of 500 study participants, n=38 did not fulfil EPAD inclusion criteria, n=34 did not have CSF or MRI biomarkers, and n=49 were not either healthy controls or in the Alzheimer spectrum and were thus excluded. Cut‐offs were 1025 pg/mL for CSF amyloid ß1,42 (A), 24 pg/mL for CSF p‐tau (T), and age‐adjusted hippocampal volume w‐score below ‐2 standard deviations for neurodegeneration (N). Out of the n=376 sample, 229 individuals were classified as healthy controls (A‐T‐N‐), 102 as showing only amyloid pathology (A+T‐N‐), 45 showing amyloid and tau pathologies (A+T+N‐), and 3 A+T+N+ were eliminated [Table 1]. The ENE battery distinguished healthy controls (A‐T‐N‐) from individuals with preclinical AD (A+T+N‐), and individuals with Alzheimer pathological changes (A+T‐N‐) from individuals with preclinical AD (A+T+N‐).ConclusionWe proposed a data‐driven framework of cut‐offs for classifying preclinical AD patients in the ATN scheme. The ENE battery scores were in line with the expected cognitive decline in the AD spectrum and increasing vascular burden was shown with progression along the AD spectrum. Potential applications include the selection of patients for secondary prevention trials, preclinical disease modelling and monitoring responses to disease‐modifying therapies.

Chronic subsyndromal depression and risk of dementia in older adults.

Subsyndromal depression is prevalent and associated with poor outcomes in late life, but its effect on the risk of dementia has barely been investigated. This study is aimed to investigate the effect of subsyndromal depression on dementia risk in cognitively normal older adults and patients with mild cognitive impairment. Data were collected from a nationwide, population-based, prospective cohort study on a randomly sampled Korean elderly population aged 60 years or older, which has been followed every 2 years. Using 6-year follow-up data of 4456 non-demented elderly, the authors examined the risk of dementia associated with late-onset subsyndromal depression using multivariate Cox proportional hazard models. After standardized diagnostic interviews, subsyndromal depression and dementia were diagnosed by the operational diagnostic criteria and Diagnostic and Statistical Manual of Mental Disorders, 4th edition criteria, respectively. Subsyndromal depression tripled the risk of dementia in non-demented elderly individuals (hazard ratio = 3.02, 95% confidence interval = [1.56, 5.85], p < 0.001). In subgroup analyses, subsyndromal depression was associated with the risk of dementia in cognitively normal participants only (hazard ratio = 4.59, 95% confidence interval = [1.20, 17.54], p = 0.026); chronic/recurrent subsyndromal depression with increasing severity during the follow-up period was associated with the risk of dementia (hazard ratio = 15.34, 95% confidence interval = [4.19, 56.18], p < 0.001). Late-onset subsyndromal depression is a potential predictor of incident dementia when it is chronic or recurrent with increasing severity in cognitively normal older adults.

Age and diet modify acute microhemorrhage outcome in the mouse brain

Cerebral microhemorrhages (CMHs) are considered as asymptomatic lesions, but might impair cognition in non-demented elderly individuals. The aging process includes poor vascular health, enhanced at midlife by metabolic disturbances upon high-fat diet (HFD). The onset of CMHs could thus have more serious consequences in midlife subjects with metabolic disturbances. This hypothesis was tested through the induction of multiple CMHs, using cyclodextrin nanoparticles injection, in mice at midlife (14 month old) or at a younger stage (5 month old) after 12 months or 3 months of normal diet or HFD (40% of animal fat) respectively. When induced at 14 months of age, CMHs were not larger but were more numerous (+25%) in mice on HFD compared with mice on normal diet. They slowed down the locomotor activity significantly but caused neither a change in the working memory nor a difference in the visual recognition memory decline. When induced at 5 months of age, CMHs provoked slighter locomotor and cognitive symptoms, regardless the diet. No spontaneous progression of CMHs toward larger hemorrhages was observed after onset when HFD was prolonged up to midlife. Consistently, no precipitated cognitive decline was observed. Middle-age plus time of metabolic disturbances represent enhanced risk factors for CMH outcome.

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.

Effects of combining exercise with long-chain polyunsaturated fatty acid supplementation on cognitive function in the elderly: a randomised controlled trial

Multifactorial lifestyle intervention is known to be more effective for ameliorating cognitive decline than single factor intervention; however, the effects of combining exercise with long-chain polyunsaturated fatty acids (LCPUFA) on the elderlies' cognitive function remain unclear. We conducted a randomised, single-masked placebo-controlled trial in non-demented elderly Japanese individuals. Participants were randomly allocated to the exercise with LCPUFA, placebo, or no exercise with placebo (control) groups. Participants in the exercise groups performed 150 min of exercise per week, comprised resistance and aerobic training, for 24 weeks with supplements of either LCPUFA (docosahexaenoic acid, 300 mg/day; eicosapentaenoic acid, 100 mg/day; arachidonic acid, 120 mg/day) or placebo. Cognitive functions were evaluated by neuropsychological tests prior to and following the intervention. The per-protocol set analysis (n = 76) revealed no significant differences between the exercise and the control groups in changes of neuropsychological tests. Subgroup analysis for participants with low skeletal muscle mass index (SMI) corresponding to sarcopenia cut-off value showed changes in selective attention, while working memory in the exercise with LCPUFA group was better than in the control group. These findings suggest that exercise with LCPUFA supplementation potentially improves attention and working memory in the elderly with low SMI.

Longitudinal Cognitive and Biomarker Measurements Support a Unidirectional Pathway in Alzheimer’s Disease Pathophysiology

BackgroundAmyloid-β (Aβ) likely plays a primary role in Alzheimer’s disease pathogenesis, but longitudinal Aβ, tau, and neurodegeneration (A/T/N) measurements in the same individuals have rarely been examined to verify the temporal dynamics of these biomarkers. MethodsIn this study, we investigated the temporal ordering of Aβ, tau, and neurodegeneration using longitudinal biomarkers in nondemented elderly individuals. A total of 395 cognitively unimpaired individuals and 204 individuals with mild cognitive impairment (320 [53%] were female) were classified into 8 A±/T±/N± categories according to the abnormal (+)/normal (–) status of Aβ (18F-florbetapir or 18F-florbetaben) positron emission tomography (PET), 18F-flortaucipir PET, and adjusted hippocampal volume (aHCV). Follow-up Aβ PET, tau PET, and aHCV measurements at 0.6 to 4.1 years were available for 35% to 63% of the sample. Baseline Aβ, tau, and aHCV were compared between different A/T/N profiles. We investigated the associations of baseline and longitudinal Aβ, tau, and neurodegeneration in relation to one another continuously. ResultsAmong T– participants, tau was higher for A+/T–/N– individuals compared with the A–/T–/N– group (p = .02). Among N– participants, neurodegeneration was worse among A+/T+/N– individuals compared with the A–/T–/N– group (p = .001). High baseline Aβ was associated (p < .001) with subsequent tau increase and high baseline tau was associated (p = .002) with subsequent aHCV decrease, whereas high tau and low aHCV at baseline were not associated with subsequent Aβ increase. ConclusionsThese findings define a sequence of pathological events in Alzheimer’s disease that support a current model of Alzheimer’s disease pathogenesis in which Aβ appears early, followed by deposition of abnormal tau aggregates and subsequent neurodegeneration.