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Brain functional and structural changes lead to cognitive decline during aging, but a high level of cognitive stimulation during life can improve cognitive performances in the older adults, forming the cognitive reserve. Noradrenaline has been proposed as a molecular link between environmental stimulation and constitution of the cognitive reserve. Taking advantage of the ability of olfactory stimulation to activate noradrenergic neurons of the locus coeruleus, we used repeated olfactory enrichment sessions over the mouse lifespan to enable the cognitive reserve buildup. Mice submitted to olfactory enrichment, whether started in early or late adulthood, displayed improved olfactory discrimination at late ages and interestingly, improved spatial memory and cognitive flexibility. Moreover, olfactory and non-olfactory cognitive performances correlated with increased noradrenergic innervation in the olfactory bulb and dorsal hippocampus. Finally, c-Fos mapping and connectivity analysis revealed task-specific remodeling of functional neural networks in enriched older mice. Long-term olfactory enrichment thus triggers structural noradrenergic plasticity and network remodeling associated with better cognitive aging and thereby forms a promising mouse model of the cognitive reserve buildup. • Long-term olfactory enrichment broadly improves cognition in older mice. • Long-term olfactory enrichment induces local expansion of noradrenergic innervation. • Long-term olfactory enrichment drives task-specific brain network remodeling. • Olfactory stimulation along the life span allows the cognitive reserve build up. [ABSTRACT FROM AUTHOR]

Lipids are essential components of brain structure and shown to affect brain function. Previous studies have shown that aging men undergo greater brain atrophy than women, but whether the associations between lipids and brain atrophy differ by sex is unclear. We examined sex differences in the associations between circulating lipids by liquid chromatography-tandem mass spectrometry and the progression of MRI-derived brain atrophy index Spatial Patterns of Atrophy for Recognition of Brain Aging (SPARE-BA) over an average of 4.7 (SD = 2.3) years in 214 men and 261 women aged 60 or older who were initially cognitively normal using multivariable linear regression, adjusted for age, race, education, and baseline SPARE-BA. We found significant sex interactions for beta-oxidation rate, short-chain acylcarnitines, long-chain ceramides, and very long-chain triglycerides. Lower beta-oxidation rate and short-chain acylcarnitines in women and higher long-chain ceramides and very long-chain triglycerides in men were associated with faster increases in SPARE-BA (accelerated brain aging). Circulating lipid profiles of accelerated brain aging are sex-specific and vary by lipid classes and structure. Mechanisms underlying these sex-specific lipid profiles of brain aging warrant further investigation. [ABSTRACT FROM AUTHOR]

The cognitive reserve (CR) hypothesis is reinforced by negative moderating effects, suggesting that those with higher CR are less reliant on brain structure for cognitive function. Previous research on CR's moderating effects yielded inconsistent results, motivating our 3 studies using UK Biobank data. Study I examined five CR proxies' moderating effects on global, lobar, and regional brain-cognition models; study II extended study I by using a larger sample size; and study III investigated age-related moderating effects on the hippocampal regions. In study I, most moderating effects were negative and none survived the multiple comparison correction, but study II identified 13 global-level models with significant negative moderating effects that survived correction. Study III showed age influenced CR proxies' moderating effects in hippocampal regions. Our findings suggest that the effects of CR proxies on brain integrity and cognition varied depending on the proxy used, brain integrity indicators, cognitive domain, and age group. This study offers significant insights regarding the importance of CR for brain integrity and cognitive outcomes. [ABSTRACT FROM AUTHOR]

The relationship between brain microstructure and aging has been the subject of intense study, with diffusion MRI perhaps the most effective modality for elucidating these associations. Here, we used the mean apparent propagator (MAP)-MRI framework, which is suitable to characterize complex microstructure, to investigate age-related cerebral differences in a cohort of cognitively unimpaired participants and compared the results to those derived using diffusion tensor imaging. We studied MAP-MRI metrics, among them the non-Gaussianity (NG) and propagator anisotropy (PA), and established an opposing pattern in white matter of higher NG alongside lower PA among older adults, likely indicative of axonal degradation. In gray matter, however, these two indices were consistent with one another, and exhibited regional pattern heterogeneity compared to other microstructural parameters, which could indicate fewer neuronal projections across cortical layers along with an increased glial concentration. In addition, we report regional variations in the magnitude of age-related microstructural differences consistent with the posterior-anterior shift in aging paradigm. These results encourage further investigations in cognitive impairments and neurodegeneration. [ABSTRACT FROM AUTHOR]

• ApoE4 is a risk factor for Alzheimer's disease. • Process of brain Aβ accumulation was analyzed with AD mouse models expressed human apoE. • ApoE4 increased Aβ42 linearly with age whereas apoE3 dramatically increased Aβ42 at a late age. • The reduced brain apoE3 in aged mouse might induce the rapid increase of brain Aβ42. • Altered gene expression in the presence of the human apoE generates distinct processes in the brain Aβ42 accumulation. Apolipoprotein E4 (apoE4) is a risk factor for Alzheimer's disease (AD). Here, we investigated brain amyloid-β (Aβ) accumulation throughout the aging process in an amyloid precursor protein (APP) knock-in (KI) mouse model of AD that expresses human APPNL-G-F with or without human apoE4 or apoE3. Brain Aβ42 levels were significantly lower in 9-month-old mice that express human isoforms of apoE than in age-matched APP-KI control mice. Linear accumulation of Aβ42 began in 5-month-old apoE4 mice, and a strong increase in Aβ42 levels was observed in 21-month-old apoE3 mice. Aβ42 levels in cerebroventricular fluid were higher in apoE3 than in apoE4 mice at 6–7 months of age, suggesting that apoE3 is more efficient at clearing Aβ42 than apoE4 at these ages. However, apoE3 protein levels were lower than apoE4 protein levels in the brains of 21-month-old apoE3 and apoE4 mice, respectively, which may explain the rapid increase in brain Aβ42 burden in apoE3 mice. We identified genes that were downregulated in a human apoE-dependent (apoE4 > apoE3) and age-dependent (apoE3 = apoE4) manner, which may regulate brain Aβ burden and/or AD progression. Analysis of gene expression in AD mouse models helps identify molecular mechanisms of pleiotropy by the human APOE gene during aging. [ABSTRACT FROM AUTHOR]

To explore how cerebral microbleeds (CMBs) accompanying mild traumatic brain injury (mTBI) reflect white matter (WM) degradation and cognitive decline, magnetic resonance images were acquired from 62 mTBI adults (imaged ∼ 7 days and ∼ 6 months post-injury) and 203 matched healthy controls. On average, mTBI participants had a count of 2.7 ± 2.6 traumatic CMBs in WM, located 6.1 ± 4.4 mm from cortex. At ∼ 6-month follow-up, 97% of CMBs were associated with significant reductions (34% ± 11%, q < 0.05) in the fractional anisotropy of WM streamlines within ∼ 1 cm of CMB locations. Male sex and older age were significant risk factors for larger reductions (q < 0.05). For CMBs in the corpus callosum, cingulum bundle, inferior and middle longitudinal fasciculi, fractional anisotropy changes were significantly and positively associated with changes in cognitive functions mediated by these structures (q < 0.05). Our findings distinguish traumatic from non-traumatic CMBs by virtue of surrounding WM alterations and challenge the assumption that traumatic CMBs are neurocognitively silent. Thus, mTBI with CMB findings can be described as a clinical endophenotype warranting longitudinal cognitive assessment. [ABSTRACT FROM AUTHOR]

• We investigate how DKI can enhance DTI findings of aging adult white matter. • Diffusivity values computed from DKI are 15%–20% greater than those computed from DTI. • A greater extent of WM shows kurtosis than diffusivity age associations (75% vs. 66%). • Overlapping diffusivity/kurtosis patterns in DKI help form biological interpretation. Studies of healthy brain aging traditionally report diffusivity patterns associated with white matter degeneration using diffusion tensor imaging (DTI), which assumes that diffusion measured at typical b-values (approximately 1000 s/mm2) is Gaussian. Diffusion kurtosis imaging (DKI) is an extension of DTI that measures non-Gaussian diffusion (kurtosis) to better capture microenvironmental processes by incorporating additional data at a higher b-value. In this study, using diffusion data (b-values of 1000 and 2000 s/mm2) from 700 UK Biobank participants aged 46–80, we investigate (1) the extent of novel information gained from adding diffusional kurtosis to diffusivity observations in aging, and (2) how conventional DTI metrics in aging compare with diffusivity metrics derived from DKI, which are corrected for kurtosis. We establish a pattern of lower kurtosis alongside higher diffusivity among older adults, with kurtosis generally being more sensitive to age than diffusivity. We also find discrepancies between diffusivity metrics derived from DTI and DKI, emphasizing the importance of accounting for non-Gaussian diffusion when interpreting age-related diffusivity patterns. [ABSTRACT FROM AUTHOR]

Prenatal nutrition may significantly impact brain aging. Results from the Dutch Famine Birth Cohort indicated that prenatal undernutrition is negatively associated with cognition, brain volumes, perfusion and structural brain aging in late life, predominantly in men. This study investigates the association between prenatal undernutrition and late-life functional brain network connectivity. In an exploratory resting-state functional magnetic resonance imaging study of 112 participants from the Dutch Famine Birth Cohort, we investigated whether the within- and between-network functional connectivity of the default mode network, salience network and central executive network differ at age 68 in men (N = 49) and women (N = 63) either exposed or unexposed to undernutrition in early gestation. Additionally, we explored sex-specific effects. Compared to unexposed participants, exposed participants revealed multiple clusters of different functional connectivity within and between the three networks studied. Sex-specific analyses suggested a pattern of network desegregation fitting with brain aging in men and a more diffuse pattern of group differences in women. This study demonstrates that associations between prenatal undernutrition and brain network functional connectivity extend late into life. [ABSTRACT FROM AUTHOR]

• Brain age was measured in 531 older community-dwelling individuals (aged ≥70 years). • Brain-predicted age difference (Brain-PAD) was defined as the difference between brain and chronological age. • Brain-PAD was associated with memory and 3-year memory change in raw analysis only. • Brain-PAD was associated with psychomotor speed even after Bonferroni correction. Brain age is a neuroimaging-based biomarker of aging. This study examined whether the difference between brain age and chronological age (brain-PAD) is associated with cognitive function at baseline and longitudinally. Participants were relatively healthy, predominantly white community-dwelling older adults (n = 531, aged ≥70 years), with high educational attainment (61% ≥12 years) and socioeconomic status (59% ≥75th percentile). Brain age was estimated from T1-weighted magnetic resonance images using an algorithm by Cole et al., 2018. After controlling for age, gender, education, depression and body mass index, brain-PAD was negatively associated with psychomotor speed (Symbol Digit Modalities Test) at baseline (Bonferroni p < 0.006), but was not associated with baseline verbal fluency (Controlled Oral Word Association Test), delayed recall (Hopkins Learning Test Revised), or general cognitive status (Mini-Mental State Examination). Baseline brain-PAD was not associated with 3-year change in cognition (Bonferroni p > 0.006). These findings indicate that even in relatively healthy older people, accelerated brain aging is associated with worse psychomotor speed, but future longitudinal research into changes in brain-PAD is needed. [ABSTRACT FROM AUTHOR]

• A lifestyle composite of smoking, alcohol consumption, diet, physical activity, and social engagement at age 40 was associated with accelerated brain aging in old age. • Brain aging and AD-brain signature in old age were worse among participants with lower age 20 cognitive ability. • Lower cognitive ability predicted better brain outcomes if lifestyle was favorable, but high cognitive ability predicted better brain outcomes regardless of lifestyle. • Favorable early midlife lifestyle may be protective against neurodegeneration and dementia risk especially among adults with lower cognitive ability. • Efforts at prevention could be prioritized earlier in midlife. We examined the influence of lifestyle on brain aging after nearly 30 years, and tested the hypothesis that young adult general cognitive ability (GCA) would moderate these effects. In the community-dwelling Vietnam Era Twin Study of Aging (VETSA), 431 largely non-Hispanic white men completed a test of GCA at mean age 20. We created a modifiable lifestyle behavior composite from data collected at mean age 40. During VETSA, MRI-based measures at mean age 68 included predicted brain age difference (PBAD), Alzheimer's disease (AD) brain signature, and abnormal white matter scores. There were significant main effects of young adult GCA and lifestyle on PBAD and the AD signature (p s ≤ 0.012), and a GCA-by-lifestyle interaction on both (p s ≤ 0.006). Regardless of GCA level, having more favorable lifestyle behaviors predicted less advanced brain age and less AD-like brain aging. Unfavorable lifestyles predicted advanced brain aging in those with lower age 20 GCA, but did not affect brain aging in those with higher age 20 GCA. Targeting early lifestyle modification may promote dementia risk reduction, especially among lower reserve individuals. [ABSTRACT FROM AUTHOR]

• Oxidative stress is involved in the progression of aging and Alzheimer's disease (AD). • Free radicals damage mitochondria, increasing production of toxic amyloid beta (Aβ). • DNA repair dysfunction is more severe in the AD brain than in the aged brain. • Inhibiting oxidation-induced epigenetic changes can improve cognition and reduce Aβ. • Long term exercise effectively reduces oxidative stress and improves cognition. Reactive oxygen species (ROS) are metabolic byproducts that are necessary for physiological function but can be toxic at high levels. Levels of these oxidative stressors increase gradually throughout the lifespan, impairing mitochondrial function and damaging all parts of the body, particularly the central nervous system. Emerging evidence suggests that accumulated oxidative stress may be one of the key mechanisms causing cognitive aging and neurodegenerative diseases such as Alzheimer's disease (AD). Here, we synthesize the current literature on the effect of neuronal oxidative stress on mitochondrial dysfunction, DNA damage and epigenetic changes related to cognitive aging and AD. We further describe how oxidative stress therapeutics such as antioxidants, caloric restriction and physical activity can reduce oxidation and prevent cognitive decline in brain aging and AD. Of the currently available therapeutics, we propose that long term physical activity is the most promising avenue for improving cognitive health by reducing ROS while promoting the low levels required for optimal function. [ABSTRACT FROM AUTHOR]

• Brain age prediction from routine clinical T2-weighted images is feasible. • We built and evaluated a prediction model with institutional clinical imaging data. • A greater white matter hyperintensity resulted in a higher predicted age difference. • Diabetes mellitus was associated with a higher predicted age difference. Our study investigated the feasibility and clinical relevance of brain age prediction using axial T2-weighted images (T2-WIs) with a deep convolutional neural network (CNN) algorithm. The CNN model was trained by 1,530 scans in our institution. The performance was evaluated by the mean absolute error (MAE) between the predicted brain age and the chronological age based on an internal test set (n =270) and an external test set (n =560). The ensemble CNN model showed an MAE of 4.22 years in the internal test set and 9.96 years in the external test set. Participants with grade 2–3 white matter hyperintensity (WMH) showed a higher corrected predicted age difference (PAD) than grade 0 WMH (posthoc p <0.001). Participants diagnosed with diabetes mellitus also had a higher corrected PAD than those without diabetes (adjusted p =0.048), although it showed no significant differences according to the diagnosis of hypertension or dyslipidemia. We suggest that routine clinical T2-WIs are feasible to predict brain age, and it might be clinically relevant according to the WMH grade and the presence of diabetes mellitus. [ABSTRACT FROM AUTHOR]

White matter fiber tracts demonstrate heterogeneous vulnerabilities to aging effects. Here, we estimated age-related differences in tract properties using UK Biobank diffusion magnetic resonance imaging data of 7167 47- to 76-year-old neurologically healthy people (3368 men and 3799 women). Tract properties in terms of generalized fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity were sampled on 76 fiber tracts; for each tract, age-related differences were estimated by fitting these indices against age in a linear model. This cross-sectional study demonstrated 4 age-difference patterns. The dominant pattern was lower generalized fractional anisotropy and higher axial diffusivity, radial diffusivity, and mean diffusivity with age, constituting 45 of 76 tracts, mostly involving the association, projection, and commissure fibers connecting the prefrontal lobe. The other 3 patterns constituted only 14 tracts, with atypical age differences in diffusion indices, and mainly involved parietal, occipital, and temporal cortices. By analyzing the large volume of diffusion magnetic resonance imaging data available from the UK Biobank, the study has provided a detailed description of heterogeneous age-related differences in tract properties over the whole brain which generally supports the myelodegeneration hypothesis. • Diffusion MRI data of 7167 neurologically healthy people aged 47–76 years were analyzed. • Age-related differences in diffusion MRI parameters of 76 tracts were characterized. • A dominant pattern of age-related difference was found in the association fibers and prefrontal tracts. • Sensorimotor and visual tracts showed distinct patterns of age-related difference suggesting different fiber organizations. • Female participants had lower generalized fractional anisotropy in some tracts than male participants of similar age. [ABSTRACT FROM AUTHOR]

Brain aging is a complex process, which involves multiple pathways including various components from cellular to molecular. This study aimed to investigate the gene expression changes in zebrafish brains through young-adult to adult, and adult to old age. RNA sequencing was performed on isolated neuronal cells from zebrafish brains. The cells were enriched in progenitor cell markers, which are known to diminish throughout the aging process. We found 176 statistically significant, differentially expressed genes among the groups, and identified a group of genes based on gene ontology descriptions, which were classified as cell adhesion molecules. The relevance of these genes was further tested in another set of zebrafish brains, human healthy, and Alzheimer's disease brain samples, as well as in Allen Brain Atlas data. We observed that the expression change of 2 genes, GJC2 and ALCAM , during the aging process was consistent in all experimental sets. Our findings provide a new set of markers for healthy brain aging and suggest new targets for therapeutic approaches to neurodegenerative diseases. • Cell adhesion molecules have differential expression during aging. • ALCAM and GJC2 expression is decreased in aging and Alzheimer's disease. • Neural cell culture from zebrafish brain reveals aging related pathways. [ABSTRACT FROM AUTHOR]

The brain-age paradigm is proving increasingly useful for exploring aging-related disease and can predict important future health outcomes. Most brain-age research uses structural neuroimaging to index brain volume. However, aging affects multiple aspects of brain structure and function, which can be examined using multimodality neuroimaging. Using UK Biobank, brain-age was modeled in n = 2205 healthy people with T1-weighted MRI, T2-FLAIR, T2∗, diffusion-MRI, task fMRI, and resting-state fMRI. In a held-out healthy validation set (n = 520), chronological age was accurately predicted (r = 0.78, mean absolute error = 3.55 years) using LASSO regression, higher than using any modality separately. Thirty-four neuroimaging phenotypes were deemed informative by the regression (after bootstrapping); predominantly gray-matter volume and white-matter microstructure measures. When applied to new individuals from UK Biobank (n = 14,701), significant associations with multimodality brain-predicted age difference (brain-PAD) were found for stroke history, diabetes diagnosis, smoking, alcohol intake and some, but not all, cognitive measures (corrected p < 0.05). Multimodality neuroimaging can improve brain-age prediction, and derived brain-PAD values are sensitive to biomedical and lifestyle factors that negatively impact brain and cognitive health. • Brain-age was predicted from 6 different neuroimaging modalities. • Combined multi-modality brain-age was more accurate than any single modality. • Thirty-four neuroimaging measures were informative for brain-age prediction. • Informative measures generally reflect brain volume and white-matter microstructure. • Brain-age was associated with stroke, diabetes, smoking, alcohol and cognition. [ABSTRACT FROM AUTHOR]

Steadily aging populations result in a growing need for research regarding age-related brain alterations and neurodegenerative pathologies. By allowing a good translation of results to humans, nonhuman primates, such as the gray mouse lemur Microcebus murinus , have gained attention in this field. Our aim was to examine correlations between atrophy-induced brain alterations and age, with special focus on sex differences in mouse lemurs. For cerebral volumetric measurements, in vivo magnetic resonance imaging was performed on 59 animals (28♀♀/31♂♂) aged between 1.0 to 11.9 years. Volumes of different brain regions, cortical thicknesses, and ventricular expansions were evaluated. Analyses revealed significant brain atrophies with increasing age, particularly around the caudate nucleus, the thalamus, and frontal, parietal, and temporo-occipital regions. Especially old females showed a strong decline in cingulate cortex thickness and had higher values of ventricular expansion, whereas cortical thickness of the splenium and occipital regions decreased mainly in males. Our study, thus, provides first evidence for sex-specific, age-related brain alterations in a nonhuman primate, suggesting that mouse lemurs can help elucidating the mechanism underlying sex disparities in cerebral aging, for which there is mixed evidence in humans. • Cerebral atrophy and age correlate in mouse lemur primates. • Some age-related alterations in the brain are sex specific. • Region-specific patterns of cortical shrinkage differ between sexes. • Females show strong ventricular expansions with age. • Males show age-related ventricular dilation only in parts of the lateral ventricles. [ABSTRACT FROM AUTHOR]

It is unclear whether alterations in cerebral pH underlie Alzheimer's disease (AD) and other dementias. We performed proton spectroscopy after oral administration of histidine in healthy young and elderly persons and in patients with mild cognitive impairment and dementia (total N = 147). We measured cerebral tissue pH and ratios of common brain metabolites in relation to phosphocreatine and creatine (Cr) in spectra acquired from the hippocampus, the white matter (WM) of the centrum semiovale, and the cerebellum. Hippocampal pH was inversely associated with age in healthy participants but did not differ between patients and controls. WM pH was low in AD and, to a lesser extent, mild cognitive impairment but not in frontotemporal dementia spectrum disorders and pure vascular dementia. Furthermore, WM pH provided incremental diagnostic value in addition to N-acetylaspartate to Cr ratio. Our study suggests that in vivo assessment of pH may be a useful marker for the differentiation between AD and other types of dementia. • Normal aging was associated with low pH in the hippocampus. • AD was associated with low pH in periventricular white matter. • The combination of metabolite ratios and pH improved diagnostic accuracy. • The question arises whether pH-modulating therapies could be beneficial in AD. [ABSTRACT FROM AUTHOR]

Brain age prediction is a machine learning method that estimates an individual's chronological age from their neuroimaging scans. Brain age indicates whether an individual's brain appears "older" than age-matched healthy peers, suggesting that they may have experienced a higher cumulative exposure to brain insults or were more impacted by those pathological insults. However, contemporary brain age models include older participants with amyloid pathology in their training sets and thus may be confounded when studying Alzheimer's disease (AD). We showed that amyloid status is a critical feature for brain age prediction models. We trained a model on T1-weighted MRI images participants without amyloid pathology. MRI data were processed to estimate gray matter density voxel-wise, which were then used to predict chronological age. Our model performed accurately comparable to previous models. Notably, we demonstrated more significant differences between AD diagnostic groups than other models. In addition, our model was able to delineate significant differences in brain age relative to chronological age between cognitively normal individuals with and without amyloid. Incorporation of amyloid status in brain age prediction models ultimately improves the utility of brain age as a biomarker for AD. • Brain age may serve as a promising, individualized biomarker of brain health. • Current brain age models may be confounded by amyloid pathology in training sets. • We have shown that amyloid status is a critical feature for brain age models. • Our model accurately predicted brain age in the training and independent test sets. • We demonstrated significant differences in brain age between AD diagnostic groups. [ABSTRACT FROM AUTHOR]

The basal levels of expression of mRNA of cytokines, interleukin-6 (IL-6) and tumor necrosis factor (TNF-alpha), in the cerebral cortex of 5 and 26 month-old male B6C3F1 mice have been compared. In addition, the responsivity of animals of differing age to an inflammatory stimulus (lipopolysaccharide, LPS) has been studied. Basal levels of both of these cytokine mRNAs were elevated in aged animals relative to the younger group. However LPS administration led to a robust increase in cytokine mRNA levels in the younger animals but in aged mice, there was either an unchanged (IL-6) or a depressed (TNF-alpha) response. Administration of dietary melatonin (200 ppm) to aged mice for 6 weeks prior to sacrifice, resulted in reduction of basal levels of cytokine mRNA to values found in the younger animals. Furthermore, following administration of LPS to melatonin fed animals, cerebral cytokine mRNA levels were significantly elevated rather than being unchanged or depressed. Taken together these findings reflect a trend in the cortices of melatonin-treated aged mice, to more closely approximate the status of younger mice. For comparative purposes, parallel studies were carried out using an immunologically active organ (spleen) and a non-neural organ with a low rate of cell turnover (heart muscle). In both these tissues, basal levels of cytokine mRNAs of animals of either age were very low, and there was a marked positive response to LPS. Dietary melatonin had no effect on the responses of TNF-alpha mRNA to LPS but attenuated the reaction of splenic IL-6 mRNA, thus bringing the response closer to that of the younger mice.

This study evaluated the effect of the alpha-2A-adrenoceptor agonist guanfacine on prefrontally mediated cognitive functions, as well as quality of life and global function in healthy older participants. One hundred twenty-three participants aged 75 years and older were randomly assigned to guanfacine 0.5 mg, 0.1 mg, or placebo daily for 12 weeks. The primary outcome measure was the change in z -score for 6 prefrontal executive function tasks over 12 weeks (PEF6). Neither dose of guanfacine improved PEF6 z -score relative to placebo. The rate of mean change (95% confidence interval) in PEF6 z -score over 12 weeks was 0.270 (0.159, 0.380) for placebo, compared with 0.121 (0.011, 0.232) for guanfacine 0.1 mg ( p = 0.06, compared to placebo) and 0.213 (0.101, 0.324) for 0.5 mg ( p = 0.47). Neither dose of guanfacine improved the quality of life or global function relative to placebo. Among common adverse events, only dry mouth was significantly more frequent on guanfacine compared to placebo. Guanfacine failed to ameliorate prefrontal cognitive function in older individuals, who were cognitively normal for age. [ABSTRACT FROM AUTHOR]

Altered inhibition-excitation balance is implicated in brain aging. We hypothesized that expression of 14 genes encoding proteins localized to synapses or interneurons would show age-related changes relative to 1 another in postmortem tissue from the prefrontal cortex of 37 individuals (18–78 years) and that synaptic or interneuron markers would be differentially correlated with human brain volumes across aging. The majority of genes examined were differentially expressed with age, most being downregulated. Expression of 3 interneuron-related genes was significantly negatively associated with age (calbindin, somatostatin, cholecystokinin), whereas 3 synapse-related genes showed significant age-related expression change ( PSD95 , GAP43 , VGLUT1 ). On covarying for 2 glial markers ( GFAP , IBA1 ), all 3 interneuron genes and 1 synaptic gene (Growth-associated protein 43) remained significant. Two genes were significantly associated with total brain volume (calbindin, complexin 2) and a marker of synaptic density (synaptophysin) was significantly associated with cortical gray matter volume. Age-related change in expression of genes involved in maintenance of inhibition-excitation balance and regulation of prefrontocortical network dynamics suggests these pathways may contribute to brain aging. [ABSTRACT FROM AUTHOR]

Negative fateful life events (FLEs) such as interpersonal conflict, death in the family, financial hardship, and serious medical emergencies can act as allostatic stressors that accelerate biological aging. However, the relationship between FLEs and neuroanatomical aging is not well understood. We examined 359 men (mean age 62 years) participating in the Vietnam Era twin study of aging (VETSA) to determine whether negative midlife FLEs are associated with advanced brain aging after controlling for physical, psychological, and lifestyle factors. At two different time points, participants were assessed for negative FLEs, health and well-being, general cognitive ability, socioeconomic status, depression, and ethnicity. Participants underwent a magnetic resonance imaging examination, and T1-weighted images were processed with FreeSurfer. Subsequent neuroanatomical measurements were entered into the Brain-Age Regression Analysis and Computation Utility software (BARACUS) to predict brain age. Having more midlife FLEs, particularly relating to interpersonal relationships, was associated with advanced predicted brain aging (i.e., higher predicted brain age relative to chronological age). This association remained after controlling for the significant covariates of alcohol consumption, cardiovascular risk, adult socioeconomic status, and ethnicity. [ABSTRACT FROM AUTHOR]

Amyloid deposits and tau-immunoreactive neurofibrillary tangles, together with neuronal and synaptic loss, are the neuropathological hallmarks of Alzheimer's disease (AD). Both proteins are present in the normal brain during aging. However, the temporal sequence of their involvement in the onset of AD pathology remains controversial. To define whether amyloid β protein deposits or tau protein lesions appear first during normal brain aging, we performed an immunohistological study on serial sections from 105 autopsy brains (age range: 40–104 years) from patients free of clinical signs of cognitive decline, using anti-tau (AT8) and anti-amyloid (4G8) antibodies in the hippocampus, entorhinal cortex, inferior temporal cortex (Brodmann area 20), prefrontal cortex (Brodmann area 9), occipital cortex (Brodmann areas 17 and 18), and in the brainstem. All cases older than 48 years displayed at least a few neurofibrillary tangles, which appeared more frequently in the entorhinal than in the transentorhinal cortex. Tau pathology in these areas preceded tau inclusions in the brainstem. Furthermore, the first site of the apparition of tau pathology is inconsistent, being the entorhinal cortex in most cases, and in fewer cases, the transentorhinal region. There was no case presenting with amyloid deposition in the absence of neurofibrillary tangles, lending evidence to the fact that neurofibrillary tangles appear earlier than amyloid plaques during normal brain aging. However, the role of amyloid in promoting tau deposition cannot be excluded in some cases but may not represent the sole mechanism of disease induction and progression. [ABSTRACT FROM AUTHOR]

Brain aging is accompanied by declining mitochondrial respiration. We hypothesized that mitochondrial morphology and dynamics would reflect this decline. Using hippocampus and frontal cortex of a segmental progeroid mouse model lacking Cockayne syndrome protein B (CSB m/m ) and C57Bl/6 (WT) controls and comparing young (2–5 months) to middle-aged mice (13–14 months), we found that complex I-linked state 3 respiration (CI) was reduced at middle age in CSB m/m hippocampus, but not in CSB m/m cortex or WT brain. In hippocampus of both genotypes, mitochondrial size heterogeneity increased with age. Notably, an inverse correlation between heterogeneity and CI was found in both genotypes, indicating that heterogeneity reflects mitochondrial dysfunction. The ratio between fission and fusion gene expression reflected age-related alterations in mitochondrial morphology but not heterogeneity. Mitochondrial DNA content was lower, and hypoxia-induced factor 1α mRNA was greater at both ages in CSB m/m compared to WT brain. Our findings show that decreased CI and increased mitochondrial size heterogeneity are highly associated and point to declining mitochondrial quality control as an initial event in brain aging. [ABSTRACT FROM AUTHOR]

Normal aging is associated with impairments in cognitive functions. These alterations are caused by diminutive changes in the biology of synapses, and ineffective neurotransmission, rather than loss of neurons. Hitherto, only a few studies, exploring molecular mechanisms of healthy brain aging in higher vertebrates, utilized synaptosomal fractions to survey local changes in aging-related transcriptome dynamics. Here we present, for the first time, a comparative analysis of the synaptosomes transcriptome in the aging mouse brain using RNA sequencing. Our results show changes in the expression of genes contributing to biological pathways related to neurite guidance, synaptosomal physiology, and RNA splicing. More intriguingly, we also discovered alterations in the expression of thousands of novel, unannotated lincRNAs during aging. Further, detailed characterization of the cleavage and polyadenylation factor I subunit 1 (Clp1) mRNA and protein expression indicates its increased expression in neuronal processes of hippocampal stratum radiatum in aging mice. Together, our study uncovers a new layer of transcriptional regulation which is targeted by aging within the local environment of interconnecting neuronal cells. [ABSTRACT FROM AUTHOR]

Individuals with Down syndrome (DS) are more likely to experience earlier onset of multiple facets of physiological aging. This includes brain atrophy, beta amyloid deposition, cognitive decline, and Alzheimer's disease—factors indicative of brain aging. Here, we employed a machine learning approach, using structural neuroimaging data to predict age (i.e., brain-predicted age) in people with DS (N = 46) and typically developing controls (N = 30). Chronological age was then subtracted from brain-predicted age to generate a brain-predicted age difference (brain-PAD) score. DS participants also underwent [ 11 C]-PiB positron emission tomography (PET) scans to index the levels of cerebral beta amyloid deposition, and cognitive assessment. Mean brain-PAD in DS participants' was +2.49 years, significantly greater than controls ( p < 0.001). The variability in brain-PAD was associated with the presence and the magnitude of PiB-binding and levels of cognitive performance. Our study indicates that DS is associated with premature structural brain aging, and that age-related alterations in brain structure are associated with individual differences in the rate of beta amyloid deposition and cognitive impairment. [ABSTRACT FROM AUTHOR]

Although a major risk factor for Alzheimer's disease (AD), the “aging” parameter is not systematically considered in preclinical validation of anti-AD drugs. To explore how aging affects neuronal reactivity to anti-AD agents, the ciliary neurotrophic factor (CNTF)–associated pathway was chosen as a model. Comparison of the neuroprotective properties of CNTF in 6- and 18-month old mice revealed that CNTF resistance in the older animals is associated with the exclusion of the CNTF-receptor subunits from rafts and their subsequent dispersion to non-raft cortical membrane domains. This age-dependent membrane remodeling prevented both the formation of active CNTF-receptor complexes and the activation of prosurvival STAT3 and ERK1/2 pathways, demonstrating that age-altered membranes impaired the reactivity of potential therapeutic targets. CNTF-receptor distribution and CNTF signaling responses were improved in older mice receiving dietary docosahexaenoic acid, with CNTF-receptor functionality being similar to those of younger mice, pointing toward dietary intervention as a promising adjuvant strategy to maintain functional neuronal membranes, thus allowing the associated receptors to respond appropriately to anti-AD agents. [ABSTRACT FROM AUTHOR]

Successful brain aging in the oldest old (≥90 years) is underexplored. This study examined cross-sectional brain morphological differences from 8th to 11th decades of life in nondemented individuals by high-resolution magnetic resonance imaging. Two hundred seventy-seven nondemented community-dwelling participants (71–103 years) from Sydney Memory and Ageing Study and Sydney Centenarian Study comprised the sample, including a subsample of 160 cognitively high-functioning elders. Relationships between age and magnetic resonance imaging–derived measurements were studied using general linear models; and structural profiles of the ≥90 years were delineated. In full sample and the subsample, significant linear negative relationship of gray matter with age was found, with the greatest age effects in the medial temporal lobe and parietal and occipital cortices. This pattern was further confirmed by comparing directly the ≥90 years to the 71–89 years groups. Significant quadratic age effects on total white matter and white matter hyperintensities were observed. Our study demonstrated heterogeneous differences across brain regions between the oldest old and young old, with an emphasis on hippocampus, temporoposterior cortex, and white matter hyperintensities. [ABSTRACT FROM AUTHOR]

The hippocampus appears commonly affected by aging and various neurologic disorders in humans, whereas little is known about age-related change in overall protein expression in this brain structure. Using the 4-plex tandem mass tag labeling, we carried out a quantitative proteomic study of the hippocampus during normal aging using postmortem brains from Chinese subjects. Hippocampal samples from 16 subjects died of non-neurological/psychiatric diseases were divided into 4 age groups: 22–49, 50–69, 70–89, and >90. Among 4582 proteins analyzed, 35 proteins were significantly elevated, whereas 25 proteins were downregulated, along with increasing age. Several upregulated proteins, including transgelin, vimentin, myosin regulatory light polypeptide 9, and calcyphosin, were further verified by quantitative Western blot analysis of hippocampal tissues from additional normal subjects. Bioinformatic analysis showed that the upregulated and downregulated proteins were largely involved in several important protein-protein interaction networks. Proteins in the electron transport chain and synaptic vesicle fusion pathway were consistently downregulated with aging, whereas proteins associated with Alzheimer's disease showed little change. Our study demonstrates substantial protein profile changes in the human hippocampus during aging, which could be of relevance to age-related loss of hippocampal functions. [ABSTRACT FROM AUTHOR]

Elucidating the molecular mechanisms of brain aging remains a significant challenge for biogerontologists. The discovery of gene regulation by microRNAs (miRNAs) has added a new dimension for examining this process; however, the full complement of miRNAs involved in brain aging is still not known. In this study, miRNA profiles of young, adult, and old rats were obtained to evaluate molecular changes during aging. High-throughput deep sequencing revealed 547 known and 171 candidate novel miRNAs that were differentially expressed among groups. Unexpectedly, miRNA expression did not decline progressively with advancing age; moreover, genes targeted by age-associated miRNAs were predicted to be involved in biological processes linked to aging and neurodegenerative diseases. These findings provide novel insight into the molecular mechanisms underlying brain aging and a resource for future studies on age-related brain disorders. [ABSTRACT FROM AUTHOR]

Increased mitochondrial hydrogen peroxide (H 2 O 2 ) is associated with Alzheimer's disease and brain aging. Peroxiredoxin 3 (Prdx3) is the key mitochondrial antioxidant defense enzyme in detoxifying H 2 O 2 . To investigate the importance of mitochondrial H 2 O 2 in age-associated cognitive decline, we compared cognition between aged (17–19 months) APP transgenic mice and APP/Prdx3 double transgenic mice (dTG) and between old (24 months) wild-type mice and Prdx3 transgenic mice (TG). Compared with aged APP mice, aged dTG mice showed improved cognition that was correlated with reduced brain amyloid beta levels and decreased amyloid beta production. Old TG mice also showed significantly increased cognitive ability compared with old wild-type mice. Both aged dTG mice and old TG mice had reduced mitochondrial oxidative stress and increased mitochondrial function. Moreover, CREB signaling, a signaling pathway important for cognition was enhanced in both aged dTG mice and old TG mice. Thus, our results indicate that mitochondrial H 2 O 2 is a key culprit of age-associated cognitive impairment, and that a reduction of mitochondrial H 2 O 2 could improve cognition by maintaining mitochondrial health and enhancing CREB signaling. [ABSTRACT FROM AUTHOR]

Abstract: Among primates, humans are uniquely vulnerable to many age-related neurodegenerative disorders. We used structural and diffusion magnetic resonance imaging (MRI) to examine the brains of chimpanzees and rhesus monkeys across each species' adult lifespan, and compared these results with published findings in humans. As in humans, gray matter volume decreased with age in chimpanzees and rhesus monkeys. Also like humans, chimpanzees showed a trend for decreased white matter volume with age, but this decrease occurred proportionally later in the chimpanzee lifespan than in humans. Diffusion MRI revealed widespread age-related decreases in fractional anisotropy and increases in radial diffusivity in chimpanzees and macaques. However, both the fractional anisotropy decline and the radial diffusivity increase started at a proportionally earlier age in humans than in chimpanzees. Thus, even though overall patterns of gray and white matter aging are similar in humans and chimpanzees, the longer lifespan of humans provides more time for white matter to deteriorate before death, with the result that some neurological effects of aging may be exacerbated in our species. [Copyright &y& Elsevier]

Abstract: Basal forebrain cholinergic neurons (BFCN), a system involved in learning and memory processes, are highly dependent on a continuous supply of biologically active nerve growth factor (NGF). Age-related cholinergic atrophy and cell loss in normal brains is apparently not complemented by reductions in the levels of NGF as could be expected. In the present work, cortical proNGF/NGF were immunoprecipitated from cortical brain homogenates from young and aged and behaviorally characterized rats and resolved with antinitrotyrosine antibodies to reveal nitration of tyrosine residues in proteins. Cortical proNGF in aged and cognitively impaired rats was found to be a target for peroxynitrite-mediated oxidative damage with correlative impact on decrease in choline acetyltransferase activity. These studies provide evidence for oxidative stress damage of NGF molecules in the cerebral cortex of cognitively impaired aged rats as previously shown in AD human brains. [Copyright &y& Elsevier]

Abstract: In normal aging, the mammalian cortex undergoes significant remodeling. Although neuromodulation by dopamine and noradrenaline in the cortex is known to be important for proper cognitive function, little is known on how cortical noradrenergic and dopaminergic presynaptic boutons are affected in normal aging. Using rats we investigated whether these two neurotransmitter systems undergo structural reorganization in aging, and if these changes correlated with cognitive loss. Young and aged rats were tested for cognitive performance using the Morris water maze. Following the behavioral characterization, the animals were sacrificed and the cortical tissue was processed for immunofluorescence using antibodies directed against tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH) to detect and discriminate noradrenergic and dopaminergic varicosities. We observed a significant increase in dopaminergic varicosities in lamina V of the anterior cingulate cortex (ACC) of aged cognitively unimpaired rats when compared to young and aged-impaired animals. In laminae II and III of the ACC, we observed a significant decrease of dopaminergic varicosities in aged-impaired animals when compared to young or aged cognitively unimpaired animals. Changes in noradrenergic varicosities never reached statistical significance in any group or brain region. The data suggests that the remodeling of mesocortical dopaminergic fibers may participate in age-associated cognitive decline. [Copyright &y& Elsevier]

Abstract: Until recently, free d-amino acids were thought to be involved only in bacterial physiology. Nevertheless, today there is evidence that d-serine, by acting as co-agonist at NMDARs, plays a role in controlling neuronal functions in mammals. Besides d-serine, another d-amino acid, d-aspartate (d-Asp), is found in the mammalian brain with a temporal gradient of occurrence: high in embryo and low in adult. In this study, we demonstrate that d-Asp acts as an endogenous NMDAR agonist, since it triggers currents via interaction with each of NR2A-D receptor subunits. According to its pharmacological features, we showed that oral administration of d-Asp strongly enhances NMDAR-dependent LTP in adulthood and, in turn, completely rescues the synaptic plasticity decay observed in the hippocampus of aged animals. Therefore, our findings suggest a tantalizing hypothesis for which this in-embryo-occurring d-amino acid, when “forced” over its physiological content, may disclose plasticity windows inside which it counteracts the age-related reduction of NMDAR signaling. [Copyright &y& Elsevier]

Abstract: The atypical amino acid d-aspartate (d-Asp) occurs at considerable amounts in the developing brain of mammals. However, during postnatal life, d-Asp levels diminish following the expression of d-aspartate oxidase (DDO) enzyme. The strict control of DDO over its substrate d-Asp is particularly evident in the hippocampus, a brain region crucially involved in memory, and highly vulnerable to age-related deterioration processes. Herein, we explored the influence of deregulated higher d-Asp brain content on hippocampus-related functions during aging of mice lacking DDO (Ddo −/−). Strikingly, we demonstrated that the enhancement of hippocampal synaptic plasticity and cognition in 4/5-month-old Ddo −/− mice is followed by an accelerated decay of basal glutamatergic transmission, NMDAR-dependent LTP and hippocampus-related reference memory at 13/14 months of age. Therefore, the precocious deterioration of hippocampal functions observed in mutants highlights for the first time a role for DDO enzyme in controlling the rate of brain aging process in mammals. [Copyright &y& Elsevier]

Abstract: Astrocytes contribute to a variety of functions in the brain, including homeostasis, synapse formation, plasticity, and metabolism. Astrocyte dysfunction may disrupt their normal role, including neuronal support, thereby contributing to neurodegenerative pathologies, including Alzheimer''s disease (AD). To understand the role of astrocytes in the pathogenesis of age-related disorders, we isolated astrocytes by laser capture microdissection, using glial fibrillary acidic protein (GFAP) as a marker, and characterized the astrocyte transcriptome at different Braak neurofibrillary tangle stages in postmortem temporal cortex samples derived from the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS) cohort, using microarray analysis. The largest number of significant, differentially expressed genes were identified when the expression profile of astrocytes from isocortical stages of neurofibrillary tangle pathology (Braak stages V–VI) were compared with entorhinal stages (Braak stages I–II). Dysregulation of genes associated with the actin cytoskeleton, proliferation, apoptosis, and ubiquitin-mediated proteolysis occurred at low Braak stages, while altered regulation of intracellular signaling pathways, including insulin, phosphatidylinositol 3-kinase (PI3K)/Akt, and mitogen-activated protein kinase (MAPK) pathways were primarily associated with high levels of Alzheimer-type pathology, and occurred at lower Braak stages in individuals with the APOEε4 allele. Our findings implicate astrocyte dysfunction in the pathogenesis of neurodegenerative pathology in the aging brain, and provide a basis for future candidate studies based on specific pathways. [Copyright &y& Elsevier]

Abstract: Brain aging is associated with a progressive decline in cognitive function though the molecular mechanisms remain unknown. Functional changes in brain neurons could be due to age-related alterations in levels of specific proteins critical for information processing. Specialized membrane microdomains known as ‘lipid rafts’ contain protein complexes involved in many signal transduction processes. This study was undertaken to determine if two-dimensional fluorescence difference gel electrophoresis (2D DIGE) analysis of proteins in synaptic membrane lipid rafts revealed age-dependent alterations in levels of raft proteins. Five pairs of young and aged rat synaptic membrane rafts were subjected to DIGE separation, followed by image analysis and identification of significantly altered proteins. Of 1046 matched spots on DIGE gels, 94 showed statistically significant differences in levels between old and young rafts, and 87 of these were decreased in aged rafts. The 41 most significantly altered (p <0.03) proteins included several synaptic proteins involved in energy metabolism, redox homeostasis, and cytoskeletal structure. This may indicate a disruption in bioenergetic balance and redox homeostasis in synaptic rafts with brain aging. Differential levels of representative identified proteins were confirmed by immunoblot analysis. Our findings provide novel pathways in investigations of mechanisms that may contribute to altered neuronal function in aging brain. [ABSTRACT FROM AUTHOR]

Abstract: Magnetic resonance imaging (MRI) findings of large white matter hyperintensities (LWMH), decreased brain volume and silent cerebral infarcts (SCI) are subclinical indices of brain ischemia and aging. Although the pathophysiology of these findings remains uncertain, extracellular matrix (ECM) remodeling, a process regulated by matrix metalloproteinases (MMPs) and their inhibitors (TIMPs), may be implicated. We evaluated the cross-sectional relations of circulating MMP-9 and TIMP-1 to these MRI indices in 583 stroke and dementia-free, Framingham Offspring participants (mean age 57 years, 58% women). Using multivariable regression MMP-9 (detectable versus non-detectable) and TIMP-1 (modeled as sex-specific quartiles) were related to LWMH (>1S.D. above age-specific mean; yes/no), SCI (yes/no) and total brain volume (ratio of parenchymal to intracranial volume, TCBVr). Mean TCBVr was 0.78 (S.D. 0.03), 13% of subjects had LWMH and 12% had SCI. Detectable MMP-9 was associated with higher prevalence of LWMH (OR 2.09, 95%confidence interval (CI) 1.00–4.37), but not with TCBVr. TIMP-1 was associated with a high prevalence of LWMH (OR for Q4 versus Q1–3: 1.83, 95%CI 1.06–3.18) and with lower mean TCBVr (Q4 associated with 0.17 S.D. units lower value relative to Q1–3; p =0.04). Neither biomarker was associated with SCI. Our findings are preliminary but if confirmed in further studies, suggest a pathophysiological role for the MMP/TIMP pathway in processes of brain ischemia and aging. [ABSTRACT FROM AUTHOR]

Abstract: Previously we showed that macrophage activation in the eye by intravitreal application of zymosan increased retinal ganglion cell (RGC) survival and axonal regeneration after optic nerve injury. It is known that the intrinsic ability of CNS neurons to survive and to regrow axons after optic nerve injury differs between developing and adult mammals. However, whether aged animals also differ in their ability to survive and regrow injured axons are not known. In this study we investigated whether the abilities of RGCs to survive and to regrow injured axons differed between rats aged 6–8, 60 and over 96 weeks, and whether macrophage responses in the eye were different at different ages. We found that the intrinsic viability of RGCs, as shown in vitro, was reduced in aged rats, but RGC viability after optic nerve injury in vivo was similar among rats of the different ages. The ability of RGCs to regrow injured axons into a peripheral nerve graft also remained similar between young and aged rats. Macrophage activation in the eye was confirmed to be beneficial and provided the basis for zymosan treatment-dependent RGC protection. However, reduced activation of macrophages in zymosan-treated eyes was seen in aged rats. Importantly, this reduced macrophage activation in aged rats led to a decreased level of RGC axonal regeneration when compared with that in young rats of the same treatment. Thus age influences the intrinsic viability of RGCs and the beneficial impact of macrophages on RGC axonal regeneration after optic nerve injury. [Copyright &y& Elsevier]

Abstract: Data mining of a large data base from the population longitudinal study named “The Conselice Study” has been the focus of the present investigation. Initially, 65 years old or older participants were interviewed, underwent medical and cognitive examination, and were followed up for 5 years: 937 subjects completed the follow-up. Relationships of 35 genetic and/or phenotypic factors with incident cognitive decline and dementia were investigated. The new mathematical approach, called the Auto Contractive Map (AutoCM), was able to show the differential importance of each variables. This new variable processing created a semantic connectivity map that: (a) preserved non-linear associations; (b) showed connection schemes; (c) captured the complex dynamics of adaptive interactions. This method, based on an artificial adaptive system, was able to define the association strength of each variable with all the others. Few variables resulted to be aggregation points and were considered as major biological hubs. Three hubs were identified in the hydroxyl-methyl-gutaryl-CoA reductase (HMGCR) enzyme, plasma cholesterol levels and age. Gene variants and cognate phenotypic variables showed differential degrees of relevance to brain aging and dementia. This data analysis method was compared with another mathematical model called mutual information relevance network and results are presented and discussed. [Copyright &y& Elsevier]

Abstract: In Alzheimer''s disease (AD), Parkinson''s disease (PD), dementia with Lewy bodies (DLB) and amyotrophic lateral sclerosis (ALS), neuroinflammatory responses are considered to contribute to neuronal injury. Recently, the innate immune receptors, toll-like receptors (TLRs) and the LPS receptor (CD14) have been related to neurodegeneration. In this study, we systematically assessed the expression of most TLRs and CD14 in AD, PD/DLB and ALS using murine models of these diseases and human post-mortem brain tissues. A common upregulation of TLR2 and CD14 was found in all three animal models. While these two receptors could also be detected in AD patient tissues, they were absent from DLB and ALS tissues. This uniform pattern of innate immune response in animal models of neurodegenerative diseases clearly indicates that this response is part of a non-specific neuroinflammatory effector phase rather than a disease-specific event. The less dynamic disease progression in humans and the location (extracellular versus intracellular) of the aggregated proteins deposits might explain the divergent results seen between animal models and human tissues. [Copyright &y& Elsevier]

Abstract: Effects of APOE genotype on age-related slopes of cortical thinning was estimated by measuring the thickness of the cerebral cortex on a point-by-point basis across the cortical mantle in 96 healthy non-demented volunteers aged 48–75 years. Fifty nine were APOE ɛ4− (no ɛ4 allele) and 37 were ɛ4+ (1 or 2 ɛ4 alleles). The genotype groups had similar age, sex and IQ. Two T1-weighted MP-RAGE sequences were averaged for each participant to yield images with high signal-to-noise ratio, and quantified using semi-automated analysis tools. ɛ4 carriers had thicker cortex than non-carriers in several frontal and temporal areas in both hemispheres, but showed a steeper age-related decline in adjacent areas. Upon comparison of the ɛ4-specific age-related thinning with previously published patterns of thinning in normal aging and Alzheimer''s disease (AD), we conclude that APOE ɛ4 may function to accelerate thinning in areas found to decline in aging (medial prefrontal and pericentral cortex), but also to initiate thinning in areas associated with AD and amyloid-β aggregation (occipitotemporal and basal temporal cortex). [Copyright &y& Elsevier]

Abstract: Age-related impairment of functionality of the central nervous system (CNS) is associated with increased susceptibility to develop many neurodegenerative diseases. Increased oxidative stress in the CNS of aged animals is manifested by increased protein oxidation, which is believed to contribute to the age-related learning and memory deficits. Glutamate dysregulation, mitochondrial dysfunction and impaired protein synthesis are observed in aged brains, along with increased protein oxidation. Interestingly, all of these age-related cellular alterations can be improved by caloric restriction (CR), which can also improve the plasticity and recovery of the CNS. Although the beneficial effects of CR on brains are well established, the mechanism(s) of its action remains unclear. In order to gain insight into the mechanism of CR in the brain, we located the brain regions that are benefited the most from reduced oxidative stress by CR. Along with other brain regions, striatum (ST) showed significantly decreased bulk protein carbonyl levels and hippocampus (HP) showed decreased bulk protein 3-nitrotyrosine (3-NT) levels in CR aged rats when compared to those of age matched controls. To determine which proteins were oxidatively modified in these brain regions, we used parallel proteomics approach to identify the proteins that are altered in oxidation and expression. The specific carbonyl levels of pyruvate kinase M2 (PKM2), α-enolase (ENO1), inositol monophosphatase (INSP1), and F1-ATPase Chain B (ATP-F1B) were significantly decreased in ST of aged CR rats. In contrast, the expression levels of phosphoglycerate kinase 1 (PKG1), inosine monophosphate cyclohydrolase (IMPCH) and F1-ATPase Chain A (ATP-F1A) were significantly increased in the ST of CR rats. In the hippocampus of CR rats, the specific 3-NT levels of malate dehydrogenase (MDH), phosphoglycerate kinase 1 (PKG1) and 14-3-3 zeta protein were significantly decreased and expression levels of DLP1 splice variant 1 (DLP1), mitochondrial aconitase (ACO2), dihydrolipoamide dehydrogenase (DLDH), neuroprotective peptide H3 (NPH3), and eukaryotic translation initiation factor 5A (eIF-5A) are increased. Moreover, an unnamed protein product (UNP1) with similar sequence to initiation factor 2 (IF-2) was decreased in the HP of CR rats. Our data support the hypothesis that CR induces a mild metabolic stress response by increasing the production of neurotrophic proteins, therefore, priming neurons against apoptosis. Moreover, our study shows that the improvement of glutamate dysregulation, mitochondrial dysfunction and protein synthesis by CR is, at least partially, due to the CR-mediated alteration of the oxidation or the expression of PKM2, ENO1, INSP1, ATP-F1B, PKG1, IMPCH, ATP-F1A MDH, PKG1 and 14-3-3 zeta protein, DLP1, ACO2, DLDH, NPH3, eIF-5A and UNP1. This study provides valuable insights into the mechanisms of the beneficial factors on brain aging by CR. [Copyright &y& Elsevier]

Abstract: The relative contribution of Alzheimer''s disease (AD) hippocampal neuronal pathology in cognitive decline is still a matter of debate. To address this issue, we performed a stereological analysis of layer II of the entorhinal cortex and the CA1 field of the hippocampus in 34 autopsy cases covering the whole spectrum of old age and Clinical Dementia Rating (CDR) scores. In both areas, the proportion of neurofibrillary tangle (NFT)-containing neurons increased steadily as a function of the CDR score. Questionable dementia was associated with a 1.9% neuronal loss in the entorhinal cortex and 26% in the CA1 field. NFT numbers predicted only 38% of the neuron number variability in the entorhinal cortex and 55% in the CA1 field. Neuron counts in the entorhinal cortex and both neuron and NFT counts in the CA1 field were significantly associated with cognitive status explaining 25% and 44% of the CDR variability, respectively. Our data reveal a dissociation between the patterns of progression of NFT and neuronal loss in the entorhinal cortex and CA1 field. Moreover, they show that less than 50% of the cognitive variability may be attributable to AD neuronal pathology in these areas. [Copyright &y& Elsevier]