We know how age affects the brain during lab-based tasks, but what about situations truer to everyday life, such as watching movies? We measured functional magnetic resonance imaging activity while participants (N = 577) from the Cambridge Centre for Ageing and Neuroscience (www.cam-can.com) watched a movie. Watching the same movie induces significant intersubject synchronization of brain activity across participants. These cross-subject correlations suggest that viewers are processing incoming information in a similar (or shared) way. We show that with advancing age, synchrony is preserved in some areas, including the language network, but decreased in others, including the medial prefrontal cortex, medial temporal lobe, and fronto-parietal network. Synchrony declines were driven by more idiosyncratic responding in older adults and were associated with regionally distinct temporal profiles and functional connectivity patterns, as well as declines in white matter integrity. These findings suggest that areas involved in language processing remain intact with age, while regions involved in attentional control and memory may show age-related declines, even in situations similar to daily life.

Metabolic and functional studies of the amyloid precursor protein (APP) in platelets have advanced our understanding of Alzheimer's disease (AD). Here we report that human platelets contain Abeta peptides, process and secrete them constitutively. Platelets generate formerly unkown Abeta-species by differential processing of APP. Release of Abeta peptides were also increased by platelet activation with thrombin, indicating the existence of a regulated exocytotic pathway. We showed that Abeta-levels, Abeta-processing patterns and Abeta-release kinetics were regulated by thrombin. In controls, release of Abeta peptide species (Abeta 1-40/42 and 1-37/38/39/) continued for more than 4 h, while thrombin activated cells ceased secretion after 1 h at large. Treatment of platelets with prostaglandine 2 slowed this process down. Intracellular Abeta peptide concentrations decreased steadily until no peptides could be detected after 20 h (control) or after 4 h (thrombin) in cultured platelets.

Increasing evidence indicates that a disturbance of normal iron homeostasis and an amyloid-β (Aβ)-iron interaction may contribute to the pathology of Alzheimer's disease (AD), whereas iron chelation could be an effective therapeutic intervention. In the present study, transgenic mice expressing amyloid precursor protein (APP) and presenilin 1 and watered with high-dose iron served as a model of AD. We evaluated the effects of intranasal administration of the high-affinity iron chelator deferoxamine (DFO) on Aβ neuropathology and spatial learning and memory deficits created in this AD model. The effects of Fe, DFO, and combined treatments were also evaluated in vitro using SHSY-5Y cells overexpressing the human APP Swedish mutation. In vivo, no significant differences in the brain concentrations of iron, copper, or zinc were found among the treatment groups. We found that high-dose iron (deionized water containing 10 mg/mL FeCl(3)) administered to transgenic mice increased protein expression and phosphorylation of APP695, enhanced amyloidogenic APP cleavage and Aβ deposition, and impaired spatial learning and memory. Chelation of iron via intranasal administration of DFO (200 mg/kg once every other day for 90 days) inhibited iron-induced amyloidogenic APP processing and reversed behavioral alterations. DFO treatment reduced the expression and phosphorylation of APP protein by shifting the processing of APP to the nonamyloidogenic pathway, and the reduction was accompanied by attenuating the Aβ burden, and then significantly promoted memory retention in APP/PS1 mice. The effects of DFO on iron-induced amyloidogenic APP cleavage were further confirmed in vitro. Collectively, the present data suggest that intranasal DFO treatment may be useful in AD, and amelioration of iron homeostasis is a potential strategy for prevention and treatment of this disease.

A long-standing question is how to best use brain morphometric and genetic data to distinguish Alzheimer's disease (AD) patients from cognitively normal (CN) subjects and to predict those who will progress from mild cognitive impairment (MCI) to AD. Here, we use a neural network (NN) framework on both magnetic resonance imaging-derived quantitative structural brain measures and genetic data to address this question. We tested the effectiveness of NN models in classifying and predicting AD. We further performed a novel analysis of the NN model to gain insight into the most predictive imaging and genetics features and to identify possible interactions between features that affect AD risk. Data were obtained from the AD Neuroimaging Initiative cohort and included baseline structural MRI data and single nucleotide polymorphism (SNP) data for 138 AD patients, 225 CN subjects, and 358 MCI patients. We found that NN models with both brain and SNP features as predictors perform significantly better than models with either alone in classifying AD and CN subjects, with an area under the receiver operating characteristic curve (AUC) of 0.992, and in predicting the progression from MCI to AD (AUC=0.835). The most important predictors in the NN model were the left middle temporal gyrus volume, the left hippocampus volume, the right entorhinal cortex volume, and the APOE (a gene that encodes apolipoprotein E) ɛ4 risk allele. Furthermore, we identified interactions between the right parahippocampal gyrus and the right lateral occipital gyrus, the right banks of the superior temporal sulcus and the left posterior cingulate, and SNP rs10838725 and the left lateral occipital gyrus. Our work shows the ability of NN models to not only classify and predict AD occurrence but also to identify important AD risk factors and interactions among them.

Understanding the time-dependent changes of biomarkers related to Alzheimer's disease (AD) is a key to assessing disease progression and measuring the outcomes of disease-modifying therapies. In this article, we validate an AD progression score model which uses multiple biomarkers to quantify the AD progression of subjects following 3 assumptions: (1) there is a unique disease progression for all subjects; (2) each subject has a different age of onset and rate of progression; and (3) each biomarker is sigmoidal as a function of disease progression. Fitting the parameters of this model is a challenging problem which we approach using an alternating least squares optimization algorithm. To validate this optimization scheme under realistic conditions, we use the Alzheimer's Disease Neuroimaging Initiative cohort. With the help of Monte Carlo simulations, we show that most of the global parameters of the model are tightly estimated, thus enabling an ordering of the biomarkers that fit the model well, ordered as: the Rey auditory verbal learning test with 30 minutes delay, the sum of the 2 lateral hippocampal volumes divided by the intracranial volume, followed (by the clinical dementia rating sum of boxes score and the mini-mental state examination score) in no particular order and at last the AD assessment scale-cognitive subscale.

Medial temporal lobe (MTL) consists of hippocampal subfields and neighboring cortices. These heterogeneous structures are differentially involved in memory, cognitive and emotional functions, and present nonuniformly distributed atrophy contributing to cognitive disorders. This study aims to examine how genetics influences Alzheimer's disease (AD) pathogenesis via MTL substructures by analyzing high-resolution magnetic resonance imaging (MRI) data. We performed genome-wide association study to examine the associations between 565,373 single nucleotide polymorphisms (SNPs) and 14 MTL substructure volumes. A novel association with right Brodmann area 36 volume was discovered in an ERC1 SNP (i.e., rs2968869). Further analyses on larger samples found rs2968869 to be associated with gray matter density and glucose metabolism measures in the right hippocampus, and disease status. Tissue-specific transcriptomic analysis identified the minor allele of rs2968869 (rs2968869-C) to be associated with reduced ERC1 expression in the hippocampus. All the findings indicated a protective role of rs2968869-C in AD. We demonstrated the power of high-resolution MRI and the promise of fine-grained MTL substructures for revealing the genetic basis of AD biomarkers.

Aging usually affects the ability to focus attention on a given task and to ignore distractors. However, aging is also associated with increased between-subject variability, and it is unclear in which features of processing older high-performing and low-performing human beings may differ in goal-directed behavior. To study involuntary shifts in attention to task-irrelevant deviant stimuli and subsequent reorientation, we used an auditory distraction task and analyzed event-related potential measures (mismatch negativity), P3a and reorienting negativity) of 35 younger, 32 older high-performing, and 32 older low-performing participants. Although both high and low performing elderly individuals showed a delayed reorienting to the primary stimulus feature, relative to young participants, poor performance of the elderly participants in processing of deviant stimuli was associated with strong involuntary attention capture by task-irrelevant features. In contrast, high performance of the elderly group was associated with intensified attentional shifting toward the target features. Thus, it appears that performance deficits in aging are due to higher distractibility in combination with deficits in the orienting-reorienting mechanisms.

Cytoarchitectural brain changes during normal aging remain poorly characterized, and it is unclear whether patterns of brain aging differ by sex. This study used restriction spectrum imaging to examine associations between age and brain microstructure in 147 community-dwelling participants (aged 56-99 years). Widespread associations with age in multiple diffusion compartments, including increased free water, decreased restricted and hindered diffusion, and reduced neurite complexity, were observed in the cortical gray matter, the white matter tracts, and the hippocampus. Age differences in cortical microstructure were largely independent of atrophy. Associations were mostly global, although foci of stronger effects emerged in the fornix, anterior thalamic radiation and commissural fibers, and the medial temporal, orbitofrontal, and occipital cortices. Age differences were stronger and more widespread for women than men, even after adjustment for education, hypertension, and body mass index. Restriction spectrum imaging may be a convenient, noninvasive tool for monitoring changes in diffusion properties that are thought to reflect reduced cellular fractions and neurite density or complexity, which occur with typical aging, and for detecting sex differences in patterns of brain aging.

In spite of extensive work, inconsistent findings and lack of specificity in most neuroimaging techniques used to examine age- and gender-related patterns in brain tissue microstructure indicate the need for additional research. Here, we performed the largest Multi-component T2 relaxometry cross-sectional study to date in healthy adults (N = 145, 18-60 years). Five quantitative microstructure parameters derived from various segments of the estimated T2 spectra were evaluated, allowing a more specific interpretation of results in terms of tissue microstructure. We found similar age-related myelin water fraction (MWF) patterns in men and women but we also observed differential male related results including increased MWF content in a few white matter tracts, a faster decline with age of the intra- and extra-cellular water fraction and its T2 relaxation time (i.e. steeper age related negative slopes) and a faster increase in the free and quasi-free water fraction, spanning the whole grey matter. Such results point to a sexual dimorphism in brain tissue microstructure and suggest a lesser vulnerability to age-related changes in women.

Clinical, genetic, and pathological findings suggest a close relationship between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We studied the patterns of cortical atrophy across the spectrum between ALS and ALS-FTD. A surface-based morphometry analysis based on an age- and sex-matched sample of 81 ALS patients and 62 healthy control subjects (HC) was conducted. In addition, we used an age-matched subsample of 57 ALS patients and 31 HC to compare cortical thickness between 3 groups of neuropsychologically characterized ALS patients: (1) cognitively unimpaired; (2) cognitively impaired; and (3) ALS-FTD patients. Compared with HC, the entire sample of patients demonstrated cortical thinning in the bilateral precentral gyrus, right precuneus, and right frontal and temporal lobes. ALS-FTD patients showed cortical thinning in regions including the frontal and temporal gyri and the posterior cingulate cortex. Cognitively impaired ALS patients showed cortical thinning in regions largely overlapping with those found in ALS-FTD, but changes were less widespread. In conclusion, the cognitive status of ALS subjects is associated with different patterns of cortical atrophy.

Growing evidence has linked cardiorespiratory fitness (CRF) to more conserved white matter (WM) microstructure. Additional research is needed to determine which WM tracts are most strongly related to CRF and if the neuroprotective effects of CRF are age-dependent. Participants were community-dwelling adults (N = 499; ages 20-85) from the open-access Nathan Kline Institute - Rockland Sample (NKI-RS) with CRF (bike test) and diffusion tensor imaging (DTI) data. Mixed-effect modeling tested the interaction between CRF and age on global (main effect across 9 tracts) and local (individual tract effects) WM microstructure. Among older participants (age ≥ 60), CRF was significantly related to whole-brain (z-score slope = 0.11) and local WM microstructure within several tracts (| z-score slope | range = 0.13 - 0.27). Significant interactions with age indicated that the CRF-WM relationship was weaker (z-score slope ≤ 0.11) and more limited (one WM tract) in younger adults. The findings highlight the importance of aerobic exercise to maintain brain health into senescence. CRF may preferentially preserve a collection of anterior and posterior WM connections related to visuomotor function.

We examined the relationship between white matter hyperintensities (WMH) burden and performance on 4 reference abilities: episodic memory, perceptual speed, fluid reasoning, and vocabulary. Cross-sectional data of 486 healthy adults from 20 to 80 years old enrolled in an ongoing longitudinal study were analyzed. A piecewise regression across age identified an inflection point at 43 years old, where WMH total volume began to increase with age. Subsequent analyses focused on participants above that age (N = 351). WMH total volume had significant inverse correlations with perceptual speed and memory. Regional measures of WMH showed inverse correlations with all reference abilities. We performed principal component analysis of the regional WMH data to create a model of principal components regression. Parietal WMH regional volume burden mediated the relationship between age and perceptual speed in simple and multiple mediation models. The principal components regression pattern associated with perceptual speed also mediated the relationship between age and perceptual speed performance. These results across the extended adult life span help clarify the influence of WMH on cognitive aging.

Although normal aging is known to reduce cortical structures globally, the effects of aging on local structures and functions of early visual cortex are less understood. Here, using standard retinotopic mapping and magnetic resonance imaging morphologic analyses, we investigated whether aging affects areal size of the early visual cortex, which were retinotopically localized, and whether those morphologic measures were associated with individual performance on visual perceptual learning. First, significant age-associated reduction was found in the areal size of V1, V2, and V3. Second, individual ability of visual perceptual learning was significantly correlated with areal size of V3 in older adults. These results demonstrate that aging changes local structures of the early visual cortex, and the degree of change may be associated with individual visual plasticity.

Several studies have investigated the differential vulnerability of hippocampal subfields during aging and Alzheimer's disease (AD). Results were often contradictory, mainly because these works were based on concatenations of cross-sectional measures in cohorts with different ages or stages of AD, in the absence of a longitudinal design. Here, we investigated 327 participants from a population-based cohort of nondemented older adults with a 14-year clinical follow-up. MRI at baseline and 4 years later were assessed to measure the annualized rates of hippocampal subfields atrophy in each participant using an automatic segmentation pipeline with subsequent quality control. On the one hand, CA4 dentate gyrus was significantly more affected than the other subfields in the whole population (CA1-3: -0.68%/year; subiculum: -0.99%/year; and CA4-DG: -1.39%/year; p < 0.0001). On the other hand, the annualized rate of CA1-3 atrophy was associated with an increased risk of developing Alzheimer's clinical syndrome over time, independently of age, gender, educational level, and ApoE4 genotype (HR = 2.0; CI 95% 1.4-3.0). These results illustrate the natural history of hippocampal subfields atrophy during aging and AD by showing that the dentate gyrus is the most vulnerable subfield to the effects of aging while the cornu-ammonis is the primary target of AD pathophysiological processes, years before symptom onset.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder typically affecting male premutation carriers with 55-200 CGG trinucleotide repeat expansions in the FMR1 gene after age 50. The aim of this study was to examine whether cerebellar and brainstem changes emerge during development or aging in late life. We retrospectively analyzed magnetic resonance imaging scans from 322 males (age 8-81 years). Volume changes in the cerebellum and brainstem were contrasted with those in the ventricles and whole brain. Compared to the controls, premutation carriers without FXTAS showed significantly accelerated volume decrease in the cerebellum and whole brain, flatter inverted U-shaped trajectory of the brainstem, and larger ventricles. Compared to both older controls and premutation carriers without FXTAS, carriers with FXTAS exhibited significant volume decrease in the cerebellum and whole brain and accelerated volume decrease in the brainstem. We therefore conclude that cerebellar and brainstem volumes were likely affected during both development and progression of neurodegeneration in premutation carriers, suggesting that interventions may need to start early in adulthood to be most effective.

With age the ability to understand speech in multitalker environments usually deteriorates. The central auditory system has to perceptually segregate and group the acoustic input into sequences of distinct auditory objects. The present study used electrophysiological measures to study effects of age on auditory stream segregation in a multitalker scenario. Younger and older adults were presented with streams of short speech stimuli. When a single target stream was presented, the occurrence of a rare (deviant) syllable among a frequent (standard) syllable elicited the mismatch negativity (MMN), an electrophysiological correlate of automatic deviance detection. The presence of a second, concurrent stream consisting of the deviant syllable of the target stream reduced the MMN amplitude, especially when located nearby the target stream. The decrease in MMN amplitude indicates that the rare syllable of the target stream was less perceived as deviant, suggesting reduced stream segregation with decreasing stream distance. Moreover, the presence of a concurrent stream increased the MMN peak latency of the older group but not that of the younger group. The results provide neurophysiological evidence for the effects of concurrent speech on auditory processing in older adults, suggesting that older adults need more time for stream segregation in the presence of concurrent speech.

Using the anti-beta-amyloid precursor protein (betaAPP) monoclonal antibodies 4G8, 6E10 and 22C11 and flow cytometry, we report that human circulating peripheral blood monocytes display surface immunoreactivity for betaAPP. In contrast, circulating lymphocytes do not possess cell surface betaAPP immunoreactivity, despite similar levels of betaAPP expression. Immunoblotting analysis showed that monocytes, but not lymphocytes, possess an 82 kDa C-terminal betaAPP fragment consistent with a processed transmembrane species. Monocyte surface betaAPP was upregulated approximately threefold by activation with lipopolysaccharide and interferon-gamma, activation did not produce detectable betaAPP on the cell surface of lymphocytes. Surface betaAPP immunoreactivity was reduced in a normal aged population compared to normal young controls (Young = 81.07 +/- 13.67 mean fluorescence units, Aged = 36.74 +/- 3.81, p < 0.01), but was significantly increased in AD subjects compared to age-matched healthy controls (AD = 60.31 +/- 7.42, p < 0.05). Our data suggest that a proportion of peripheral A beta may be derived from monocyte/macrophages, and that defects in brain cell processing of betaAPP in AD may be shared by this readily accessible peripheral cell.

Fractal dimensionality (FD) measures the complexity within the folds and ridges of cortical and subcortical structures. We tested the degree that FD might provide a new perspective on the atrophy-compensation hypothesis: age or disease-related atrophy causes a compensatory neural response in the form of increased brain activity in the prefrontal cortex to maintain cognition. Brain structural and functional data were collected from 63 middle-aged and older adults and 18 young-adult controls. Two distinct patterns of FD were found that separated cortical from subcortical structures. Subcortical FD was more strongly negatively correlated with age than cortical FD, and cortical FD was negatively associated with brain activity during memory retrieval in medial and lateral parietal cortices uniquely in middle-aged and older adults. Multivariate analyses revealed that the lower FD/higher brain activity pattern was associated with poorer cognition-patterns not present in young adults, consistent with compensation. Bayesian analyses provide further evidence against the modal interpretation of the atrophy-compensation hypothesis in the prefrontal cortex-a key principle found in some neurocognitive theories of aging.

Measures of core cognitive processes (fluid abilities) are highly correlated with measures of knowledge (crystallized abilities) in healthy adults. In early stages of Alzheimer's disease (AD), fluid abilities, however, decline more rapidly than crystallized abilities. We hypothesized that cognitively normal older adults who evidenced lower fluid ability compared with crystallized ability (an ability discrepancy) would show evidence of early AD neuropathology indexed via in vivo measures of amyloid-beta (Aβ) deposition and cortical thickness in AD-vulnerable regions. A sample of older adults (n = 112) aged 65 to 89 underwent a cognitive battery, structural magnetic resonance imaging, and a subset (n = 75) also completed positron emission tomography scanning to measure Aβ deposition using F-18 Florbetapir. Of this sample, 60 older adults (43 with available positron emission tomography scans) evidenced a discrepancy where fluid ability was lower than crystallized ability. The magnitude of the ability discrepancy was independently associated with a greater Aβ deposition and thinner cortex in AD-vulnerable regions, as well as age. The data suggest that such a discrepancy may be a marker of preclinical AD.

The mechanisms underlying superior cognitive performance in some older adults are poorly understood. We used a multimodal approach to characterize imaging and cognitive features of 26 successful agers (SA; defined by superior episodic memory ability) and 103 typical older adults. Cortical thickness was greater in multiple regions in SA including right anterior cingulate and prefrontal cortex and was related to baseline memory performance. Similarly, hippocampal volume was greater in SA and associated with baseline memory. SA also had lower white matter hypointensity volumes and faster processing speed. While PiB burden did not differ, there was a significant group interaction in the relationship between age and PiB such that older SA individuals were less likely to have high brain β-amyloid. Over time, memory performance in typical older adults declined more rapidly than in SA, although there was limited evidence for different rates of brain atrophy. These findings indicate that superior memory in aging is related to greater cortical and white matter integrity as well as slower decline in memory performance.