ArticleLiterature Review

Session II: Mechanisms of Age-Related Cognitive Change and Targets for Intervention: Neural Circuits, Networks, and Plasticity

May 2012
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 67(7):747-53

DOI:10.1093/gerona/gls111

Source
PubMed

Authors:

Claudia Kawas

University of California, Irvine

John H Morrison

Icahn School of Medicine at Mount Sinai

Patricia Reuter-Lorenz

University of Michigan

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Age-related changes in neural circuits, neural networks, and their plasticity are central to our understanding of age changes in cognition and brain structure and function. This paper summarizes selected findings on these topics presented at the Cognitive Aging Summit II. Specific areas discussed were synaptic vulnerability and plasticity, including the role of different types of synaptic spines, and hormonal effects in the dorsolateral prefrontal cortex of nonhuman primates, the impact of both compensatory processes and dedifferentiation on demand-dependent differences in prefrontal activation in relation to age and performance, the role of vascular disease, indexed by white matter signal abnormalities, on prefrontal activation during a functional magnetic resonance imaging-based cognitive control paradigm, and the influence of amyloid-β neuropathology on memory performance in older adults and the networks of brain activity underlying variability in performance. A greater understanding of age-related changes in brain plasticity and neural networks in healthy aging and in the presence of underlying vascular disease or amyloid pathology will be essential to identify new targets for intervention. Moreover, this understanding will assist in promoting the utilization of existing interventions, such as lifestyle and therapeutic modifiers of vascular disease.

Greater Anteroposterior Default Mode Network Functional Connectivity in Long-Term Elderly Yoga Practitioners

Article

Full-text available

Jul 2019

Large-scale brain networks exhibit changes in functional connectivity during the aging process. Recent literature data suggests that Yoga and other contemplative practices may revert, at least in part, some of the aging effects in brain functional connectivity, including the Default Mode Network (DMN). The aim of this cross-sectional investigation was to compare resting-state functional connectivity of the medial prefrontal cortex (MPFC) and posterior cingulate cortex-precuneus (PCC-Precuneus) in long-term elderly Yoga practitioners and healthy paired Yoga-naïve controls. Two paired groups: yoga (Y-20 women, Hatha Yoga practitioners; practicing a minimum of twice a week with a frequency of at least 8 years) and a control group (C-20 women, Yoga-naïve, matched by age, years of formal education, and physical activity) were evaluated for: Mini Mental State Examination (MMSE), Beck Depression Inventory (BDI), Instrumental Activities of Daily Living (IADL), and open-eyes resting-state functional magnetic resonance imaging (fMRI)-seed to voxel connectivity analysis (CONN toolbox 17.f) with pre-processing-realignment and unwarping, slice-timing correction, segmentation, normalization, outlier detection, and spatial filtering. The analysis included a priori regions of interest (ROI) of DMN main nodes-MPFC and PCC-Precuneus. There was no difference between groups in terms of: age, years of formal education, MMSE, BDI and IADL. The Yoga group had a higher correlation between MPFC and the right angular gyrus (AGr), compared to the controls. Elderly women with at least 8 years of yoga practice presented greater intra-network anteroposterior brain functional connectivity of the DMN. This finding may contribute to the understanding of the influences of practicing Yoga for a healthier cognitive aging process.

Improvement of Attention, Executive Functions, and Processing Speed in Elderly Women as a Result of Involvement in the Nordic Walking Training Program and Vitamin D Supplementation

Article

Full-text available

Jun 2019

Research indicates that life satisfaction declines with age, and cognitive abilities are gradually reduced-mainly attentional functioning and cognitive processing speed. Therefore, scientists seek to find protective factors and test possible intervention programs; moderately intensive physical activity stands out as particularly promising. In this context, we evaluated the influence of Nordic Walking training supported by vitamin D supplementation (as this nutrient is especially deficient in older people in Poland) on the cognitive and psychological functioning of elderly women. A total of 52 healthy elderly women took part in a Nordic Walking training program complemented by vitamin D supplementation. Cognitive functioning was assessed with the Trail Making Test and the D2 Test of Attention. Quality of life and severity of depressive symptoms were measured with the Short Form Health Survey and the Beck Depression Inventory 2. Significant improvements in all aspects of cognitive functioning was observed (p = 0.01-0.47). The study also showed a decrease in depressive symptoms (p = 0.026). Physical activity and adequate levels of vitamin D can be the key factors in maintaining self-reliance in old age. Involvement in Nordic Walking training, supported by vitamin D supplementation, can strengthen the cognitive functioning of older people-reflected in higher attentional capabilities, better executive functions, and improved cognitive processing speed.

THE DESCRIPTION OF INDEPENDENCE LEVEL OF POST-STROKE PATIENTS

Article

Jan 2022

Background: The main source of disability that prevents individuals from being independent in doing everyday activities is functional movement disorders caused by bodily weakness in stroke conditions. This study aims to find out the level of independence of post-stroke patients. Methods: This study employs a descriptive quantitative approach based on the level of independence, type of stroke, and the side of the brain that is affected by stroke patients in Jakarta. Physiotherapists served as the enumerators for the study, which lasted for two months. The data were collected by observing and interviewing patients using the Functional Independent Measure (FIM) instrument. Results: A total of 101 stroke patients, including 78 ischemic stroke patients and 23 hemorrhagic stroke patients, were included in this study. A total of 40 individuals have left hemispheric lesions, of which 35 have ischemic types and 5 have hemorrhagic types. The overall number of patients with right hemisphere lesions is 61; of these, 43 have ischemic types and 18 have hemorrhagic types. Hemorrhagic stroke has a level of independence of 4.16 (SD + 1.06), while the ischemic stroke has a level of independence of 4.69 (SD +0.80). Ischemic stroke patients have a higher total FIM score than hemorrhagic stroke patients. Conclusion: Patients with ischemic stroke have a better level of independence than those with hemorrhagic stroke.

Relations of Metabolic Health and Obesity to Brain Aging in Young to Middle‐Aged Adults

Article

Full-text available

Mar 2022

Background We aimed to evaluate the association between metabolic health and obesity and brain health measured via magnetic resonance imaging and neurocognitive testing in community dwelling adults. Methods and Results Framingham Heart Study Third Generation Cohort members (n=2170, 46±9 years of age, 54% women) without prevalent diabetes, stroke, dementia, or other neurologic conditions were grouped by metabolic unhealthiness (≥2 criteria for metabolic syndrome) and obesity (body mass index ≥30 kg/m ² ): metabolically healthy (MH) nonobese, MH obese, metabolically unhealthy (MU) nonobese, and MU obese. We evaluated the relationships of these groups with brain structure (magnetic resonance imaging) and function (neurocognitive tests). In multivariable‐adjusted analyses, metabolically unhealthy individuals (MU nonobese and MU obese) had lower total cerebral brain volume compared with the MH nonobese referent group (both P <0.05). Additionally, the MU obese group had greater white matter hyperintensity volume ( P =0.004), whereas no association was noted between white matter hyperintensity volume and either groups of metabolic health or obesity alone. Obese individuals had less favorable cognitive scores: MH obese had lower scores on global cognition, Logical Memory‐Delayed Recall and Similarities tests, and MU obese had lower scores on Similarities and Visual Reproductions‐Delayed tests (all P ≤0.04). MU and obese groups had higher free water content and lower fractional anisotropy in several brain regions, consistent with loss of white matter integrity. Conclusions In this cross‐sectional cohort study of younger to middle‐aged adults, poor metabolic health and obesity were associated with structural and functional evidence of brain aging. Improvement in metabolic health and obesity may present opportunities to improve long‐term brain health.

Declines in grip strength may indicate early changes in cognition in healthy middle-aged adults

Article

Full-text available

Apr 2020
PLOS ONE

Declining grip strength is an indicator of cognitive loss in older individuals but it has not been explored people younger than 65 years old. The purpose of this study was to investigate the relationship between grip strength and specific cognitive tests known to decline with mild cognitive impairment in young and middle-aged adults. Declines in cognitive performance in middle-aged adults may provide evidence that these changes occur earlier than previously reported. A cross sectional design was used to compare differences between young and middle-aged healthy adults and to investigate associations between cognitive and grip strength measures within groups. Healthy young (20–30 years old) and middle-aged (45–65 years old) adults completed five cognitive tests including the Stroop, California Verbal Learning Test, Symbol Digit Modalities Test, Trail Making Tests and the Controlled Oral Word Association Test. All participants completed right and left maximum grip strength measures. Middle-aged adults performed significantly worse on right and left grip strength and the Stroop test (p<0.05) when compared to the younger group. There were no significant relationships among grip strength and cognitive performance at the whole-group level or within the younger-age group; however, weaker grip strength was significantly associated with poorer Controlled Oral Word Association Test total cluster (r = 0.458; p < .05) and Stroop interference (r = 0.471; p < .05) scores in the middle-aged group. Findings from this study suggest that cognitive changes may occur earlier than previously thought (prior to age 65). Weaker grip strength was significantly associated with poorer function in two of the cognitive measures in the middle-age group, suggesting that some domains of cognition, specifically semantic categorization and executive function, may be particularly sensitive to age-related changes.

Article

Full-text available

Oct 2019

Objective: The excitability of cerebral cortical cells, neural pathway, and neural networks, as well as their plasticity, are key to our exploration of age-related changes in brain structure and function. The combination of transcranial magnetic stimulation (TMS) with electromyography (EMG) can be applied to the primary motor cortex; it activates the underlying neural group and passes through the corticospinal pathway, which can be quantified using EMG. This meta-analysis aimed to analyze changes in cortical excitability and plasticity in healthy elderly individuals vs. young individuals through TMS-EMG. Methods: The Cochrane Library, Medline, and EMBASE databases were searched to identify eligible trials published from database inception to June 3, 2019. The Cochrane Risk of Bias Tool and improved Jadad scale were used to assess the methodological quality. A meta-analysis of the comparative effects was conducted using the Review Manager 5.3 software and Stata 14.0 software. Results: The pooled results revealed that the resting motor threshold values in the elderly group were markedly higher than those reported in the young group (mean difference [MD]: −2.35; 95% confidence interval [CI]: −3.69 to −1.02]; p < (0.00001). The motor evoked potential amplitude significantly reduced in the elderly group vs. the young group (MD: 0.18; 95% CI: 0.09–0.27; p < 0.0001). Moreover, there was significantly longer motor evoked potential latency in the elderly group (MD: −1.07; 95% CI: −1.77 to −0.37]; p =(0.003). There was no significant difference observed in the active motor threshold between the elderly and young groups (MD: −1.52; 95% CI: −3.47 to −0.42]; p =(0.13). Meanwhile, only two studies reported the absence of adverse events. Conclusion: We found that the excitability of the cerebral cortex declined in elderly individuals vs. young individuals. The findings of the present analysis should be considered with caution owing to the methodological limitations in the included trials. Additional high-quality studies are warranted to validate our findings.

Effects of Different Cognitive Trainings on Amnestic Mild Cognitive Impairment in the Elderly: A One-Year Longitudinal Functional Magnetic Resonance Imaging (MRI) Study

Article

Full-text available

Aug 2018
MED SCI MONITOR

Background Cognitive training has been focused on the interventions of amnestic mild cognitive impairment (aMCI) in recent years, with poor understanding. Material/Methods The study participants with aMCI were screened in a previous intervention trial. Functional magnetic resonance imaging (fMRI) was adopted to investigate effects of single-domain cognitive training (SDCT) and multi-domain cognitive training (MDCT) on aMCI and to explore potential mechanisms. Results There were significant differences in the grey matter volume of the middle frontal gyrus, superior parietal lobule, inferior temporal gyrus, fusiform gyrus, and ventral V3 between the MDCT/SDCT group and the control group (P<0.05). Regional homogeneity (ReHo) increased significantly in the right and left inferior frontal gyrus as well as in the left and right precentral gyrus after intervention in the MDCT group and the SDCT group. ReHo increased significantly in the right and left lingual gyrus of the MDCT group and the control group. ReHo reduced significantly in the right middle temporal gyrus of the MDCT group but increased significantly in the left middle temporal gyrus in the SDCT group and the control group. The voxel of grey matter in the precuneus was positively related to the language scores on RBANS (Repeatable Battery for the Assessment of Neuropsychological Status), and amygdala, fusiform gyrus, and hippocampus also had a positive relationship with delayed memory scores in RBANS of the MDCT group. In the MDCT group, the attention and reasoning scores were also positively related to the ReHo of middle temporal gyrus. Conclusions Both MDCT and SDCT may improve the aMCI at brain functional and structural levels; however, the MDCT group exhibited higher ReHo values in middle temporal gyrus and superior occipital gyrus. Also, it was confirmed that MDCT leads to better results than SDCT, showing a significant correlation of cognitive functions such as attention, memory, reasoning, and visual-spatial ability.

The electric field distributions in anatomical head models during transcranial direct current stimulation for post-stroke rehabilitation

Article

Dec 2016

Purpose: The lack of knowledge of the electric field distribution inside the brain of stroke patients receiving transcranial direct current stimulation (tDCS) calls for estimating it computationally. Moreover, the impact on this distribution of a novel clinical management approach which involves secondary motor areas (SMA) in stroke rehabilitation needs to be evaluated. Finally, the differences in the electric field distributions due to gender and age need to be investigated. Methods: This work presents the development of two different anatomical models (young adult female and elderly male) with an ischemic stroke region of spherical volume 10 cm(3) or 50 cm(3) , using numerical models of the Virtual Population (ViP). The stroke phase was considered as acute or chronic, resulting in different electrical properties of the area. Two different electrode montages were used - One over the lesion area and the contralateral supra-orbital region and the other over the SMA and the contralateral supra-orbital region. A quasi-electrostatic solver was used to numerically solve the Laplace equation with the finite-difference technique. Both the 99th percentile of the electric field intensity distribution ("E peak value") and the percentage of the tissue volumes with electric field intensity over 50% and 70% of the E peak value were assessed inside the target areas of the primary motor cortex (M1) and the SMA, as well as in other brain tissues (hypothalamus and cerebellum). Results: In the acute phase of an ischemic stroke, the normalized electric field intensity distributions do not differ noticeably compared to those in the brain of a healthy person (mean square difference < 2%). The difference becomes larger (up to 4.5%) for the chronic phase of a large ischemic lesion. Moreover, the maximum values of the induced electric field in the tissues in the SMA are almost equal for both electrode montages. The peak values of the electric field distribution ("E peak values") in cerebellum and hypothalamus for both electrode montages are rather small but different from those of healthy patients. The largest difference of 21% decrease with respect to a healthy subject was noticed in the elder adult model with a large chronic lesion. The comparison of the different electrode montages shows that the use of a stimulating electrode over the affected area creates larger values of the electric field in M1, by up to 26% for a small chronic lesion in the young female model. On the contrary, the montage does not affect considerably (change less than 8%) the E peak values in the SMA. This implies that for exciting M1, the M1-Fp2 montage should be favored. Conclusions: The presence and the phase of an ischemic stroke lesion, as well as the configuration of electrode montages affect the distribution and the maximum value of the electric field induced in tissues. Moreover, patients whom seem to benefit most from tDCS are those in the chronic phase of an ischemic stroke, since contrasts in the tissue conductivity result in a higher electric field induced around the lesion volume, which could stimulate the remaining healthy tissue in the area.

Workplace health promotion for older workers: A systematic literature review

Article

Full-text available

Sep 2016
BMC HEALTH SERV RES

Background Aging of the workforce is a growing problem. As workers age, their physical, physiological and psychosocial capabilities change. Keeping older workers healthy and productive is a key goal of European labor policy and health promotion is a key to achieve this result. Previous studies about workplace health promotion (WHP) programs are usually focused on the entire workforce or to a specific topic. Within the framework of the EU-CHAFEA ProHealth65+ project, this paper aims to systematically review the literature on WHP interventions specifically targeted to older workers (OWs). Methods This systematic review was conducted by making a comprehensive search of MEDLINE, ISI Web of Science, SCOPUS, The Cochrane Library, CINAHL and PsychINFO databases. Search terms included ageing (and synonyms), worker (and synonyms), intervention (and synonyms), and health (and synonyms). The search was limited to papers in English or Italian published between January, 1st 2000 and May, 31st 2015. Relevant references in the selected articles were also analyzed. ResultsOf the 299 articles initially identified as relating to the topic, 18 articles met the inclusion criteria. The type, methods and outcome of interventions in the WHP programs retrieved were heterogenous, as was the definition of the age at which a worker is considered to be ‘older’. Most of the available studies had been conducted on small samples for a limited period of time. Conclusion Our review shows that, although this issue is of great importance, studies addressing WHP actions for OWs are few and generally of poor quality. Current evidence fails to show that WHP programs improve the work ability, productivity or job retention of older workers. In addition, there is limited evidence that WHP programs are effective in improving lifestyles and concur to maintain the health and well-being of older workers. There is a need for future WHP programs to be well-designed so that the effectiveness and cost-benefit of workplace interventions can be properly investigated.

Conditioned Likelihoods Using Bifurcation Continuation in Inverse Modeling of Dynamical Systems

Article

Sep 2012

The Morris-Lecar (ML) model has applications to neuroscience and cognition. A simple network consisting of a pair of synaptically coupled ML neurons can exhibit a wide variety of deterministic behaviors including asymmetric amplitude state (AAS), equal amplitude state (EAS), and steady state (SS). In addition, in the presence of noise this network can exhibit mixed-mode oscillations (MMO), which represent the system being stochastically driven between these behaviors. In this paper, we develop a method to specifically estimate the parameters representing the coupling strength (gsyn) and the applied current (Iapp) of two reciprocally coupled and biologically similar neurons. This method employs conditioning the likelihood on cumulative power and mean voltage. Conditioning has the potential to improve the identifiability of the estimation problem. Conditioning likelihoods are typically much simpler to model than the explicit joint distribution, which several studies have shown to be difficult or impossible to determine analytically. We adopt a rejection sampling procedure over a closed defined region determined by bifurcation continuation analyses. This rejection sampling procedure is easily embedded within the proposal distribution of a Bayesian Markov chain Monte Carlo (MCMC) scheme and we evaluate its performance. This is the first report of a Bayesian parameter estimation for two reciprocally coupled Morris-Lecar neurons, and we find a proposal utilizing rejection sampling reduces parameter estimate bias relative to naive sampling. Application to stochastically coupled ML neurons is a future goal.

Walking ability to predict future cognitive decline in old adults: A scoping review

Article

Feb 2016

Early identification of individuals at risk for cognitive decline may facilitate the selection of those who benefit most from interventions. Current models predicting cognitive decline include neuropsychological and/or biological markers. Additional markers based on walking ability might improve accuracy and specificity of these models because motor and cognitive functions share neuroanatomical structures and psychological processes. We reviewed the relationship between walking ability at one point of (mid)life and cognitive decline at follow-up. A systematic literature search identified 20 longitudinal studies. The average follow-up time was 4.5 years. Gait speed quantified walking ability in most studies (n=18). Additional gait measures (n=4) were step frequency, variability and step-length. Despite methodological weaknesses, results revealed that gait slowing (0.68-1.1 m/sec) preceded cognitive decline and the presence of dementia syndromes (maximal odds and hazard ratios of 10.4 and 11.1, respectively). The results indicate that measures of walking ability could serve as additional markers to predict cognitive decline. However, gait speed alone might lack specificity. We recommend gait analysis, including dynamic gait parameters, in clinical evaluations of patients with suspected cognitive decline. Future studies should focus on examining the specificity and accuracy of various gait characteristics to predict future cognitive decline.

Association of arterial stiffness with progression of subclinical brain and cognitive disease

Article

Jan 2016

Objective: We tested whether abnormal arterial stiffness and blood pressure would be associated with progression of brain aging measured by brain MRI and neurocognitive testing. Methods: Framingham Offspring Cohort participants (n = 1,223, 61 ± 9 years, 56% women) without previous stroke or dementia underwent applanation tonometry, brain MRI, and neurocognitive testing at examination 7 (1998-2001). Follow-up brain MRI and neurocognitive testing was performed at examination 8 (2005-2008, mean interval 6.4 ± 1.3 years). We related examination 7 inverse-transformed carotid-femoral pulse wave velocity (iCFPWV), central pulse pressure (CPP), and mean arterial pressure to changes in the following variables between examinations 7 and 8: total cerebral brain volume, white matter hyperintensity volume, and performance on executive function and abstraction tasks, the Trail Making Test, Parts B and A (ΔTrails B-A), and Similarities tests. Results: Higher baseline iCFPWV and CPP were associated with greater progression of neurocognitive decline (iCFPWV and ΔTrails B-A association: SD unit change in outcome variable per SD change in tonometry variable [β] ± SE = 0.10 ± 0.04, p = 0.019; CPP and ΔSimilarities association: -0.08 ± 0.03, p = 0.013). Higher mean arterial pressure, but not iCFPWV or CPP, was associated with increase in white matter hyperintensity volume ([β ± SE] 0.07 ± 0.03, p = 0.017). No tonometry measures were associated with change in cerebral brain volume. Conclusions: In middle-aged and older adults without evidence of clinical stroke or dementia, elevated arterial stiffness and pressure pulsatility are associated with longitudinal progression of subclinical vascular brain injury and greater neurocognitive decline. Treatments to reduce arterial stiffness may potentially reduce the progression of neurovascular disease and cognitive decline.

Cognitive training can reduce the rate of cognitive aging: A neuroimaging cohort study

Article

Full-text available

Jan 2016
BMC Geriatr

The neural mechanisms underlying the restorative effects of cognitive training on aging brains remain unclear. To address this issue, we examined the relationship between changes in spontaneous brain activity and cognitive performance that occur after cognitive training. Participants were older adults who were part of a randomized control trial within a larger longitudinal cognitive training study. We conducted single-domain and multi-domain cognitive training in two respective intervention groups. Participants were trained for 1 h, twice a week, for 12 weeks. Cognition was assessed in all participants and magnetic resonance images were obtained at baseline and 1 year after training. To assess spontaneous fluctuations in brain activity, we acquired resting-state fMRI data. Two indices—functional entropy and time-domain entropy—were used to measure the effects of training. Functional entropy increases with aging, and indicates disruptions in functional conectivity. Time-domain entropy decreases with aging, and indicates structural alterations in the brain and blood-flow reduction. Seventy participants completed the study: 26 in the multi-domain cognitive training group (70.38 ± 3.30 yrs), 27 in single-domain group (70.48 ± 3.93 yrs), and 17 in a control group (68.59 ± 3.24 yrs). Functional entropy increased significantly less in the multi-domain (p = 0.047) and single-domain groups (p = 9.51 × 10 −4 ) compared with the control group. In the multi-domain group, this was true in the paracentral lobule (p = 0.004, Bonferroni corrected p < 0.05). Time-domain entropy also improved with training. Compared with controls, time-domain entropy in the multi-domain group decreased less in the inferior frontal gyrus pars opercularis (p = 3.59 × 10 −4 ), the medial part of superior frontal gyrus (p = 1.17 × 10 −5 ), and the thalamus (p = 4.72 × 10 −5 ), while that in the single-domain group decreased less in the cuneus (p = 2.58 × 10 −4 , Bonferroni corrected p < 0.05). Additionally, changes in regional entropy for some regions such as hippocampus significantly correlated with improvements in cognitive performance. Cognitive training can induce plastic changes in neural functional connectivity of healthy older people, and these changes may underlie the positive effect of cognitive training. Trial registration ChiCTR-TRC-08000732 (Date of registration: 5th November, 2008).

Aging, Motor Skill, and the Energy Cost of Walking: Implications for the Prevention and Treatment of Mobility Decline in Older Persons

Article

Sep 2014
J GERONTOL A-BIOL

Background: Age-associated neural changes profoundly affect the biomechanics and energetics of walking, increase energy cost, and require novel approaches to exercise that focus on motor learning theory. Methods: We present a conceptual framework for motor skill in walking, its effect on the energy cost of walking, and the influence of the aging brain. Results: Motor learning theory and practice can be incorporated into interventions to promote skilled, energy efficient walking in older people. Conclusions: An extensive literature on motor skill and motor learning, derived from neuroscience, sports medicine, and neurorehabilitation, can be applied to problems of walking in late life.

Structural Imaging Measures of Brain Aging

Article

Full-text available

Aug 2014
NEUROPSYCHOL REV

During the course of normal aging, biological changes occur in the brain that are associated with changes in cognitive ability. This review presents data from neuroimaging studies of primarily "normal" or healthy brain aging. As such, we focus on research in unimpaired or nondemented older adults, but also include findings from lifespan studies that include younger and middle aged individuals as well as from populations with prodromal or clinically symptomatic disease such as cerebrovascular or Alzheimer's disease. This review predominantly addresses structural MRI biomarkers, such as volumetric or thickness measures from anatomical images, and measures of white matter injury and integrity respectively from FLAIR or DTI, and includes complementary data from PET and cognitive or clinical testing as appropriate. The findings reveal highly consistent age-related differences in brain structure, particularly frontal lobe and medial temporal regions that are also accompanied by age-related differences in frontal and medial temporal lobe mediated cognitive abilities. Newer findings also suggest that degeneration of specific white matter tracts such as those passing through the genu and splenium of the corpus callosum may also be related to age-related differences in cognitive performance. Interpretation of these findings, however, must be tempered by the fact that comorbid diseases such as cerebrovascular and Alzheimer's disease also increase in prevalence with advancing age. As such, this review discusses challenges related to interpretation of current theories of cognitive aging in light of the common occurrence of these later-life diseases. Understanding the differences between "Normal" and "Healthy" brain aging and identifying potential modifiable risk factors for brain aging is critical to inform potential treatments to stall or reverse the effects of brain aging and possibly extend cognitive health for our aging society.

Building a pipeline to discover and validate novel therapeutic targets and lead compounds for Alzheimer's disease

Article

Feb 2014

Cognitive decline, Alzheimer's disease (AD) and other causes are major public health problems worldwide. With changing demographics, the number of persons with dementia will increase rapidly. The treatment and prevention of AD and other dementias, therefore, is an urgent unmet need. There have been considerable advances in understanding the biology of many age-related disorders that cause dementia. Gains in understanding AD have led to the development of ante-mortem biomarkers of traditional neuropathology and the conduct of several phase III interventions in the amyloid-β cascade early in the disease process. Many other intervention strategies are in various stages of development. However, efforts to date have met with limited success. A recent National Institute on Aging Research Summit led to a number of requests for applications. One was to establish multi-disciplinary teams of investigators who use systems biology approaches and stem cell technology to identify a new generation of AD targets. We were recently awarded one of three such grants to build a pipeline that integrates epidemiology, systems biology, and stem cell technology to discover and validate novel therapeutic targets and lead compounds for AD treatment and prevention. Here we describe the two cohorts that provide the data and biospecimens being exploited for our pipeline and describe the available unique datasets. Second, we present evidence in support of a chronic disease model of AD that informs our choice of phenotypes as the target outcome. Third, we provide an overview of our approach. Finally, we present the details of our planned drug discovery pipeline.

A novel approach to rapidly prevent age-related cognitive decline

Article

Full-text available

Oct 2013
AGING CELL

The loss of cognitive function is a pervasive and often debilitating feature of the aging process for which there are no effective therapeutics. We hypothesized that a novel metal chaperone (PBT2; Prana Biotechnology, Parkville, Victoria, Australia) would enhance cognition in aged rodents. We show here that PBT2 rapidly improves the performance of aged C57Bl/6 mice in the Morris water maze, concomitant with increases in dendritic spine density, hippocampal neuron number and markers of neurogenesis. There were also increased levels of specific glutamate receptors (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-d-aspartate), the glutamate transporter (VGLUT1) and glutamate itself. Markers of synaptic plasticity [calmodulin-dependent protein kinase II (CaMKII) and phosphorylated CaMKII, CREB, synaptophysin] were also increased following PBT2 treatment. We also demonstrate that PBT2 treatment results in a subregion-specific increase in hippocampal zinc, which is increasingly recognized as a potent neuromodulator. These data demonstrate that metal chaperones are a novel approach to the treatment of age-related cognitive decline.

Long-Term Effects of Serial Anodal tDCS on Motion Perception in Subjects with Occipital Stroke Measured in the Unaffected Visual Hemifield

Article

Full-text available

Jun 2013
FRONT HUM NEUROSCI

Transcranial direct current stimulation (tDCS) is a novel neuromodulatory tool that has seen early transition to clinical trials, although the high variability of these findings necessitates further studies in clinically relevant populations. The majority of evidence into effects of repeated tDCS is based on research in the human motor system, but it is unclear whether the long-term effects of serial tDCS are motor-specific or transferable to other brain areas. This study aimed to examine whether serial anodal tDCS over the visual cortex can exogenously induce long-term neuroplastic changes in the visual cortex. However, when the visual cortex is affected by a cortical lesion, up-regulated endogenous neuroplastic adaptation processes may alter the susceptibility to tDCS. To this end, motion perception was investigated in the unaffected hemifield of subjects with unilateral visual cortex lesions. Twelve subjects with occipital ischemic lesions participated in a within-subject, sham-controlled, double-blind study. MRI-registered sham or anodal tDCS (1.5 mA, 20 min) was applied on five consecutive days over the visual cortex. Motion perception was tested before and after stimulation sessions and at 14- and 28-day follow-up. After a 16-day interval an identical study block with the other stimulation condition (anodal or sham tDCS) followed. Serial anodal tDCS over the visual cortex resulted in an improvement in motion perception, a function attributed to MT/V5. This effect was still measurable at 14- and 28-day follow-up measurements. Thus, this may represent evidence for long-term tDCS-induced plasticity and has implications for the design of studies examining the time course of tDCS effects in both the visual and motor systems.

Hemispheric Differences in Ischemic Stroke: Is Left-Hemisphere Stroke More Common?

Article

Full-text available

Apr 2013

Background and purpose: Understanding the mechanisms underlying stroke can aid the development of therapies and improve the final outcome. The purposes of this study were to establish whether there are characteristic mechanistic differences in the frequency, severity, functional outcome, and mortality between left- and right-hemisphere ischemic stroke and, given the velocity differences in the carotid circulation and direct branching of the left common carotid artery from the aorta, whether large-vessel ischemia (including cardioembolism) is more common in the territory of the left middle cerebral artery. Methods: Trial cohorts were combined into a data set of 476 samples. Using Trial of Org 10172 in Acute Stroke Treatment criteria, ischemic strokes in a total 317 patients were included in the analysis. Hemorrhagic stroke, stroke of undetermined etiology, cryptogenic stroke, and bilateral ischemic strokes were excluded. Laterality and vascular distribution were correlated with outcomes using a logistic regression model. The etiologies of the large-vessel strokes were atherosclerosis and cardioembolism. Results: The overall event frequency, mortality, National Institutes of Health Stroke Scale (NIHSS) score, Glasgow Coma Scale score, and rate of mechanical thrombectomy interventions differed significantly between the hemispheres. Left-hemispheric strokes (54%) were more common than right-hemispheric strokes (46%; p=0.0073), and had higher admission NIHSS scores (p=0.011), increased mortality (p=0.0339), and higher endovascular intervention rates (p≤0.0001). ischemic strokes were more frequent in the distribution of the left middle cerebral artery (122 vs. 97; p=0.0003) due to the higher incidence of large-vessel ischemic stroke in this area (p=0.0011). Conclusions: Left-hemispheric ischemic strokes appear to be more frequent and often have a worse outcome than their right-hemispheric counterparts. The incidence of large-vessel ischemic strokes is higher in the left middle cerebral artery distribution, contributing to these hemispheric differences. The hemispheric differences exhibit a nonsignificant trend when strokes in the middle cerebral artery distribution are excluded from the analysis.

Neuropathological approaches to cerebral aging and neuroplasticity

Article

Full-text available

Mar 2013

Cerebral aging is a complex and heterogenous process related to a large variety of molecular changes involving multiple neuronal networks, due to alterations of neurons (synapses, axons, dendrites, etc), particularly affecting strategically important regions, such as hippocampus and prefrontal areas. A substantial proportion of nondemented, cognitively unimpaired elderly subjects show at least mild to moderate, and rarely even severe, Alzheimer-related lesions, probably representing asymptomatic preclinical Alzheimer's disease, and/or mixed pathologies. While the substrate of resilience to cognitive decline in the presence of abundant pathologies has been unclear, recent research has strengthened the concept of cognitive or brain reserve, based on neuroplasticity or the ability of the brain to manage or counteract age-related changes or pathologies by reorganizing its structure, connections, and functions via complex molecular pathways and mechanisms that are becoming increasingly better understood. Part of neuroplasticity is adult neurogenesis in specific areas of the brain, in particular the hippocampal formation important for memory function, the decline of which is common even in "healthy" aging. To obtain further insights into the mechanisms of brain plasticity and adult neurogenesis, as the basis for prevention and potential therapeutic options, is a major challenge of modern neurosciences.

Systematic Review of Parameters of Stimulation, Clinical Trial Design Characteristics, and Motor Outcomes in Non-Invasive Brain Stimulation in Stroke

Article

Full-text available

Nov 2012

Introduction: Repetitive Transcranial Magnetic Stimulation (rTMS) and Transcranial Direct Current Stimulation are two powerful non-invasive neuromodulatory therapies that have the potential to alter and evaluate the integrity of the corticospinal tract. Moreover, recent evidence has shown that brain stimulation might be beneficial in stroke recovery. Therefore, investigating and investing in innovative therapies that may improve neurorehabilitative stroke recovery are next steps in research and development.Methods: This article presents an up-to-date systematic review of the treatment effects of rTMS and tDCS on motor function. A literary search was conducted, utilizing search terms stroke and transcranial stimulation. Items were excluded if they failed to: (1) include stroke patients, (2) study motor outcomes, or (3) include rTMS/tDCS as treatments. Other exclusions included: (1) reviews, editorials, and letters, (2) animal or pediatric populations, (3) case reports or sample sizes < or = 2 patients, and (4) primary outcomes of dysphagia, dysarthria, neglect, or swallowing.Results: Investigation of PubMed English Database prior to 01/01/2012 produced 695 applicable results. Studies were excluded based on the aforementioned criteria, resulting in 50 remaining studies. They included 1314 participants (1282 stroke patients and 32 healthy subjects) evaluated by motor function pre- and post- tDCS or rTMS. Heterogeneity among studies’ motor assessments was high and could not be accounted for by individual comparison. Pooled effect sizes for the impact of post-treatment improvement revealed consistently demonstrable improvements after tDCS and rTMS therapeutic stimulation. Most studies provided limited follow-up for long-term effects.Conclusions: It is apparent from the available studies that noninvasive stimulation may enhance motor recovery and may lead to clinically-meaningful functional improvements in the stroke population.

Yoga and Aging: Neurobiological Benefits

Chapter

Full-text available

Feb 2022

Governments and societies need to be prepared to confront population aging. Such preparation includes policies that can improve quality of life, functional capacity, and health of the general population, encouraging a more active and healthier lifestyle. Normal aging is associated with changes in brain structure and function, which may cause behavioral and cognitive impairments. It is important to understand which changes make some individuals healthier than others. Yoga has been associated with improved quality of life, cognition, and physical health as well as brain functional and structural changes.

Neurochemical Aspects of Frontotemporal Dementia

Chapter

Jan 2019

Akhlaq A. Farooqui

Neurochemical Aspects of Dementia

Chapter

Jan 2019

Akhlaq A. Farooqui

Assessment of Gait as a Diagnostic Tool for Patients with Dementia

Article

Full-text available

May 2017

The association between cognition and handgrip strength among the elderly: An integrative review

Article

Full-text available

Nov 2016

The objective of this study is to identify researches that associated cognition and handgrip strength among the elderly. This is a bibliographic review, based on an integrative approach of articles published in the last five years, indexed in the PubMed, Lilacs and Scopus databases. Inclusion criteria were: observational or experimental studies with a sample of elderly people (aged 60 years or more); assessment of muscular strength using a manual dynamometer; seniors who had at least one cognitive assessment instrument. At the end of the search 10 articles were selected to examine cognitive function and statistical results in the sample. It was observed that most of the research was conducted among the elderly aged over 75 and the Mini Mental State Examination (MMSE) was identified as the scale most commonly used for global cognitive assessment. A significant association was identified between alterations in cognition and reduction of handgrip strength (HGS) in 90% of the articles included in this study. Results of this review suggest the influence of cognitive impairment on the muscular strength of the elderly, which can affect aspects of their functional capacity and consequent dependence. © 2016, Associacao Brasileira de Pos - Graduacao em Saude Coletiva. All rights reserved.

Ausgewählte altersbedingte Erkrankungen

Chapter

Jan 2016

Alte Menschen sind häufig von mehreren altersbedingten Beeinträchtigungen und Erkrankungen gleichzeitig betroffen (Multimorbidität), was die Untersuchung und das Verständnis der Verknüpfung zwischen der Alterung als dem entscheidenden Risikofaktor und einzelnen Syndromen schwierig macht. In einigen Kapiteln dieses Buchs wurden schon Verbindungen zwischen den molekularen Mechanismen der Alterung und der Pathogenese altersassoziierter Krankheiten aufgezeigt. Hier nun liegt der Fokus auf der Alzheimer‐Krankheit (AD, Alzheimer’s disease) und Krebs. Während Krebs mittlerweile in vielen Fällen pharmakologisch und/oder chirurgisch erfolgreich behandelt und manchmal sogar geheilt werden kann, ist AD noch immer eine unheilbare, tödlich verlaufende Erkrankung. Wie bei fast keiner anderen Krankheit ist das Auftreten von AD strikt mit dem Alter verknüpft und lässt einen starken Anstieg der Zahl der Krankheitsfälle für unsere alternde Gesellschaft erwarten. Die Autoren sind der Überzeugung, dass die eigentlichen Ursachen der Alzheimer‐Krankheit nur identifiziert werden können, wenn die Biochemie alternder Neuronen verstanden wird, speziell im Kontext bekannter Risikofaktoren.

Selected Age-Related Disorders

Chapter

Dec 2014

Aged human individuals are frequently affected by various age-related impairments and disorders at once (multimorbidity) making it difficult to investigate and understand the link between aging as key risk factor and single syndromes. In some chapters of this book links have been identified between molecular mechanisms of aging and the pathogenesis of human disorders in the elderly. Here, the focus is put on Alzheimers disease (AD) and cancer. While cancer in many cases can successfully be treated and sometimes even cured by pharmacology and/or surgery, AD is still an incurable deadly disease. Like almost no other disorder the onset of AD is strictly associated with higher age and experiences a strong increase in case numbers in our aging society. The authors are convinced that the actual causes of AD can only be identified when the biochemistry of the aging neuron is unraveled, especially in the context of well-known life-time risk factors.

Sleep and physical activity as modifiable risk factors in age-associated cognitive decline

Article

Nov 2015

The number of older adults over the age of 65 is rapidly increasing. This change in demographics will not only increase the prevalence of chronic medical issues, but also result in higher rates of age-associated cognitive decline. Mechanisms for age-related cognitive decline are unclear, although many persons show Alzheimer’s disease pathology, changes to cerebral blood flow, inflammation, and structural changes such as atrophy and increased white matter lesions. Increased levels of physical activity and exercise have been found to benefit older adults’ cognitive functioning through changes in brain volume and cerebral blood flow. However, these studies are unable to explain the cognitive benefits of physical activity and exercise in the absence of improvement in brain structure or blood flow, suggesting other moderating factors. An unexamined factor that may link physical activity/exercise and cognition in older adults is improved sleep. Poor sleep has already been found to contribute to cognitive decline and to improve through increased physical activity or exercise in older adults. To date, few studies have examined the relationship among cognition, physical activity/exercise, and sleep. It is unknown if sleep is a moderator for the cognitive benefits of physical activity in older adults. This review proposes sleep as a potential moderator between cognitive function and physical activity/exercise by way of cerebral blood flow. Clinical implications and future areas of research will also be discussed.

Insights into Age-Related Cognitive Decline: Coupling Neurophysiological and Behavioral Approaches

Article

Dec 2015

A major goal of research in systems and behavioral neuroscience today is to understand how our brains produce the complex and diverse behaviors that reflect what we refer to as cognition. Tremendous gains have been made over the past century in understanding the neural bases of behavior. These include insights into the basic cellular mechanisms of information processing and storage, and the identification of brain circuits critical to specific behaviors. Some studies have focused on how such neuronal networks develop in early life, reach full functional maturity, and change during aging. Defining the factors that determine successful versus pathological cognitive aging is a particularly important goal because, in most developed countries, the fastest growing segment of the population is those over 85 years of age. Although there has been significant improvement in the precision of the cognitive test batteries developed for humans across the life span, as well as improvements in the resolution and specificity of brain imaging methods, animal models of cognitive aging continue to play a critical role in revealing the brain mechanisms responsible for normal behavioral function. The use of such animal models is most productive when the cognitive operations studied depend on brain structures whose function is conserved across evolution. The circular platform spatial memory task (“Barnes Maze”) was developed to be sensitive to the function of specific brain circuits within the temporal lobe hypothesized to be important for memory in both humans and rodents, and likely to change with age. This chapter provides a personal account of the development of the circular platform task and a historical perspective regarding the overall goal for the design to develop an effective task for aged animals that minimizes task demand stress and ensures sensitivity to even small changes in the cognitive domain investigated. Detailed discussion in this chapter includes how past and newer research have converged, and have uncovered relations between memory and place cell functioning in the hippocampus by coupling neurophysiological and behavioral methodologies. This approach has allowed great insight into the processes underlying learning and memory, and has been particularly fruitful in elucidating the underpinnings of age-related cognitive decline.

Rehabilitación cognitiva en daño cerebral adquirido: variables que median en la respuesta al tratamiento

Article

Apr 2015
Rehabilitacion

Objetivo Identificar qué variables se relacionaban con la respuesta a un programa de rehabilitación cognitiva en una población de pacientes con daño cerebral adquirido. Material y métodos En este estudio retrospectivo participaron 528 pacientes con daño cerebral adquirido que recibieron rehabilitación cognitiva en nuestro centro entre febrero de 2008 y enero de 2013. Mediante análisis de regresión logística se analizó la respuesta al tratamiento (variable dependiente). La respuesta al tratamiento se calculó a partir de las diferencias entre las exploraciones neuropsicológicas pre- y post-tratamiento para las variables atención, memoria y funciones ejecutivas. Resultados La edad en el momento de la lesión (OR=0,97; 95% CI: 0,96-0,98) y el lugar donde se realizó el tratamiento (OR=0,45; 95% CI: 0,27-0,73) se asociaron positivamente con una mejor respuesta al tratamiento para el índice atencional. En el caso del índice mnésico fueron la edad (OR=0,98; 95% CI: 0,96-0,99), etiología (OR=0,63; 95% CI: 0,39-1) y lugar de realización del tratamiento (OR=0,48; 95% CI: 0,29-0,79); tales variables también resultaron significativas para el índice ejecutivo. Conclusiones Los resultados sugieren que parte de las diferencias interindividuales observadas en la respuesta al tratamiento cognitivo en pacientes con daño cerebral adquirido podrían ser explicadas por las variables edad, etiología y lugar de realización del tratamiento.

Physical activity and cognitive function in individuals over 60 years of age: A systematic review

Article

Full-text available

Apr 2014
Clin Interv Aging

It is unclear whether physical activity in later life is beneficial for maintenance of cognitive function. We performed a systematic review examining the effects of exercise on cognitive function in older individuals, and present possible mechanisms whereby physical activity may improve cognition. Sources consisted of PubMed, Medline, CINAHL, the Cochrane Controlled Trials Register, and the University of Washington, School of Medicine Library Database, with a search conducted on August 15, 2012 for publications limited to the English language starting January 1, 2000. Randomized controlled trials including at least 30 participants and lasting at least 6 months, and all observational studies including a minimum of 100 participants for one year, were evaluated. All subjects included were at least 60 years of age. Twenty-seven studies met the inclusion criteria. Twenty-six studies reported a positive correlation between physical activity and maintenance or enhancement of cognitive function. Five studies reported a dose-response relationship between physical activity and cognition. One study showed a nonsignificant correlation. The preponderance of evidence suggests that physical activity is beneficial for cognitive function in the elderly. However, the majority of the evidence is of medium quality with a moderate risk of bias. Larger randomized controlled trials are needed to clarify the association between exercise and cognitive function and to determine which types of exercise have the greatest benefit on specific cognitive domains. Despite these caveats, the current evidence suggests that physical activity may help to improve cognitive function and, consequently, delay the progression of cognitive impairment in the elderly.

Neurocognitive Aging and the Compensation Hypothesis

Article

Full-text available

Jun 2008

The most unexpected and intriguing result from functional brain imaging studies of cognitive aging is evidence for age-related overactivation: greater activation in older adults than in younger adults, even when performance is age-equivalent. Here we examine the hypothesis that age-related overactivation is compensatory and discuss the compensation-related utilization of neural circuits hypothesis (CRUNCH). We review evidence that favors a compensatory account, discuss questions about strategy differences, and consider the functions that may be served by overactive brain areas. Future research directed at neurocognitively informed training interventions may augment the potential for plasticity that persists into the later years of the human lifespan.

Working Memory, Comprehension, and Aging: A Review and a New View

Article

Full-text available

Dec 1988
Psychol Learn Motiv

Publisher Summary This chapter discusses the theoretical and empirical literature that addresses aging and discourse comprehension. A series of five studies guided by a particular working memory viewpoint regarding the formation of inferences during discourse processing is described in the chapter. Compensatory strategies may be used with different degrees of likelihood across the life span largely as a function of efficiency with which inhibitory mechanisms function because these largely determine the facility with which memory can be searched. The consequences for discourse comprehension in particular may be profound because the establishment of a coherent representation of a message hinges on the timely retrieval of information necessary to establish coreference among certain critical ideas. Discourse comprehension is an ideal domain for assessing limited capacity frameworks because most models of discourse processing assume that multiple components, demanding substantially different levels of cognitive resources, are involved. For example, access to a lexical representation from either a visual array or an auditory message is virtually capacity free.

The Cortical Signature of Alzheimer's Disease: Regionally Specific Cortical Thinning Relates to Symptom Severity in Very Mild to Mild AD Dementia and is Detectable in Asymptomatic Amyloid-Positive Individuals

Article

Full-text available

Mar 2009
CEREB CORTEX

Alzheimer's disease (AD) is associated with neurodegeneration in vulnerable limbic and heteromodal regions of the cerebral cortex, detectable in vivo using magnetic resonance imaging. It is not clear whether abnormalities of cortical anatomy in AD can be reliably measured across different subject samples, how closely they track symptoms, and whether they are detectable prior to symptoms. An exploratory map of cortical thinning in mild AD was used to define regions of interest that were applied in a hypothesis-driven fashion to other subject samples. Results demonstrate a reliably quantifiable in vivo signature of abnormal cortical anatomy in AD, which parallels known regional vulnerability to AD neuropathology. Thinning in vulnerable cortical regions relates to symptom severity even in the earliest stages of clinical symptoms. Furthermore, subtle thinning is present in asymptomatic older controls with brain amyloid binding as detected with amyloid imaging. The reliability and clinical validity of AD-related cortical thinning suggests potential utility as an imaging biomarker. This “disease signature” approach to cortical morphometry, in which disease effects are mapped across the cortical mantle and then used to define ROIs for hypothesis-driven analyses, may provide a powerful methodological framework for studies of neuropsychiatric diseases.

Amyloid-β Associated Cortical Thinning in Clinically Normal Elderly

Article

Full-text available

Jun 2011
ANN NEUROL

Both amyloid-β (Aβ) deposition and brain atrophy are associated with Alzheimer's disease (AD) and the disease process likely begins many years before symptoms appear. We sought to determine whether clinically normal (CN) older individuals with Aβ deposition revealed by positron emission tomography (PET) imaging using Pittsburgh Compound B (PiB) also have evidence of both cortical thickness and hippocampal volume reductions in a pattern similar to that seen in AD. A total of 119 older individuals (87 CN subjects and 32 patients with mild AD) underwent PiB PET and high-resolution structural magnetic resonance imaging (MRI). Regression models were used to relate PiB retention to cortical thickness and hippocampal volume. We found that PiB retention in CN subjects was (1) age-related and (2) associated with cortical thickness reductions, particularly in parietal and posterior cingulate regions extending into the precuneus, in a pattern similar to that observed in mild AD. Hippocampal volume reduction was variably related to Aβ deposition. We conclude that Aβ deposition is associated with a pattern of cortical thickness reduction consistent with AD prior to the development of cognitive impairment.

Age Differences in the Neural Representation of Working Memory Revealed by Multi-Voxel Pattern Analysis

Article

Full-text available

Nov 2010
FRONT HUM NEUROSCI

Working memory function declines across the lifespan. Computational models of aging attribute such memory impairments to reduced distinctiveness between neural representations of different mental states in old age, a phenomenon termed dedifferentiation. These models predict that neural distinctiveness should be reduced uniformly across experimental conditions in older adults. In contrast, the Compensation-Related Utilization of Neural Circuits Hypothesis (CRUNCH) model predicts that the distinctiveness of neural representations should be increased in older adults (relative to young adults) at low levels of task demand but reduced at high levels of demand. The present study used multi-voxel pattern analysis to measure the effects of age and task demands on the distinctiveness of the neural representations of verbal and visuospatial working memory. Neural distinctiveness was estimated separately for memory encoding, maintenance, and retrieval, and for low, medium, and high memory loads. Results from sensory cortex during encoding and retrieval were consistent with the dedifferentiation hypothesis: distinctiveness of visual cortical representations during these phases was uniformly reduced in older adults, irrespective of memory load. However, maintenance-related responses in prefrontal and parietal regions yielded a strikingly different pattern of results. At low loads, older adults showed higher distinctiveness than younger adults; at high loads, this pattern reversed, such that distinctiveness was higher in young adults. This interaction between age group and memory load is at odds with the dedifferentiation hypothesis but consistent with CRUNCH. In sum, our results provide partial support for both dedifferentiation- and compensation-based models; we argue that comprehensive theories of cognitive aging must incorporate aspects of both models to fully explain complex patterns of age-related neuro-cognitive change.

The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia

Article

Full-text available

Sep 2010
ACTA NEUROPATHOL

Costantino Iadecola

There is increasing evidence that cerebrovascular dysfunction plays a role not only in vascular causes of cognitive impairment but also in Alzheimer's disease (AD). Vascular risk factors and AD impair the structure and function of cerebral blood vessels and associated cells (neurovascular unit), effects mediated by vascular oxidative stress and inflammation. Injury to the neurovascular unit alters cerebral blood flow regulation, depletes vascular reserves, disrupts the blood-brain barrier, and reduces the brain's repair potential, effects that amplify the brain dysfunction and damage exerted by incident ischemia and coexisting neurodegeneration. Clinical-pathological studies support the notion that vascular lesions aggravate the deleterious effects of AD pathology by reducing the threshold for cognitive impairment and accelerating the pace of the dementia. In the absence of mechanism-based approaches to counteract cognitive dysfunction, targeting vascular risk factors and improving cerebrovascular health offers the opportunity to mitigate the impact of one of the most disabling human afflictions.

Selective Changes in Thin Spine Density and Morphology in Monkey Prefrontal Cortex Correlate with Aging-Related Cognitive Impairment

Article

Full-text available

Jun 2010
J NEUROSCI

Age-associated memory impairment (AAMI) occurs in many mammalian species, including humans. In contrast to Alzheimer's disease (AD), in which circuit disruption occurs through neuron death, AAMI is due to circuit and synapse disruption in the absence of significant neuron loss and thus may be more amenable to prevention or treatment. We have investigated the effects of aging on pyramidal neurons and synapse density in layer III of area 46 in dorsolateral prefrontal cortex of young and aged, male and female rhesus monkeys (Macaca mulatta) that were tested for cognitive status through the delayed non-matching-to-sample (DNMS) and delayed response tasks. Cognitive tests revealed an age-related decrement in both acquisition and performance on DNMS. Our morphometric analyses revealed both an age-related loss of spines (33%, p < 0.05) on pyramidal cells and decreased density of axospinous synapses (32%, p < 0.01) in layer III of area 46. In addition, there was an age-related shift in the distribution of spine types reflecting a selective vulnerability of small, thin spines, thought to be particularly plastic and linked to learning. While both synapse density and the overall spine size average of an animal were predictive of number of trials required for acquisition of DNMS (i.e., learning the task), the strongest correlate of behavior was found to be the head volume of thin spines, with no correlation between behavior and mushroom spine size or density. No synaptic index correlated with memory performance once the task was learned.

Cognition, Reserve, and Amyloid Deposition in Normal Aging

Article

Full-text available

Oct 2009
ANN NEUROL

To determine whether amyloid deposition is associated with impaired neuropsychological (NP) performance and whether cognitive reserve (CR) modifies this association. In 66 normal elderly controls and 17 patients with Alzheimer disease (AD), we related brain retention of Pittsburgh Compound B (PiB) to NP performance and evaluated the impact of CR using education and American National Adult Reading Test intelligence quotient as proposed proxies. We found in the combined sample of subjects that PiB retention in the precuneus was inversely related to NP performance, especially in tests of memory function, but also in tests of working memory, semantic processing, language, and visuospatial perception. CR significantly modified the relationship, such that at progressively higher levels of CR, increased amyloid deposition was less or not at all associated with poorer neuropsychological performance. In a subsample of normal controls, both the main effect of amyloid deposition of worse memory performance and the interaction with CR were replicated using a particularly challenging memory test. Amyloid deposition is associated with lower cognitive performance both in AD patients and in the normal elderly, but the association is modified by CR, suggesting that CR may be protective against amyloid-related cognitive impairment.

Age Differences in Prefontal Recruitment During Verbal Working Memory Maintenance Depend on Memory Load

Article

Full-text available

Apr 2010

Positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) studies have revealed age-related under-activation, where older adults show less regional brain activation compared to younger adults, as well as age-related over-activation, where older adults show greater activation compared to younger adults. These differences have been found across multiple task domains, including verbal working memory (WM). Curiously, both under-activation and over-activation of dorsolateral prefrontal cortex (DLPFC) have been found for older adults in verbal WM tasks. Here, we use event-related fMRI to test the hypothesis that age-related differences in activation depend on memory load (the number of items that must be maintained). Our predictions about the recruitment of prefrontal executive processes are based on the Compensation-Related Utilization of Neural Circuits Hypothesis (CRUNCH; Reuter-Lorenz and Cappell, 2008). According to this hypothesis, more neural resources are engaged by older brains to accomplish computational goals completed with fewer resources by younger brains. Therefore, seniors are more likely than young adults to show over-activations at lower memory loads, and under-activations at higher memory loads. Consistent with these predictions, in right DLPFC, we observed age-related over-activation with lower memory loads despite equivalent performance accuracy across age groups. In contrast, with the highest memory load, older adults were significantly less accurate and showed less DLPFC activation compared to their younger counterparts. These results are considered in relation to previous reports of activation-performance relations using similar tasks, and are found to support the viability of CRUNCH as an account of age-related compensation and its potential costs.

Aging, Training, and the Brain: A Review and Future Directions

Article

Full-text available

Oct 2009
NEUROPSYCHOL REV

As the population ages, the need for effective methods to maintain or even improve older adults' cognitive performance becomes increasingly pressing. Here we provide a brief review of the major intervention approaches that have been the focus of past research with healthy older adults (strategy training, multi-modal interventions, cardiovascular exercise, and process-based training), and new approaches that incorporate neuroimaging. As outcome measures, neuroimaging data on intervention-related changes in volume, structural integrity; and functional activation can provide important insights into the nature and duration of an intervention's effects. Perhaps even more intriguingly, several recent studies have used neuroimaging data as a guide to identify core cognitive processes that can be trained in one task with effective transfer to other tasks that share the same underlying processes. Although many open questions remain, this research has greatly increased our understanding of how to promote successful aging of cognition and the brain.

Disruption of Functional Connectivity in Clinically Normal Older Adults Harboring Amyloid Burden

Article

Full-text available

Oct 2009
J NEUROSCI

Amyloid deposition is present in 20-50% of nondemented older adults yet the functional consequences remain unclear. The current study found that amyloid accumulation is correlated with functional disruption of the default network as measured by intrinsic activity correlations. Clinically normal participants (n = 38, aged 60-88 years) were characterized using (11)C-labeled Pittsburgh Compound B positron emission tomography imaging to estimate fibrillar amyloid burden and, separately, underwent functional magnetic resonance imaging (fMRI). The integrity of the default network was estimated by correlating rest-state fMRI time courses extracted from a priori regions including the posterior cingulate, lateral parietal, and medial prefrontal cortices. Clinically normal participants with high amyloid burden displayed significantly reduced functional correlations within the default network relative to participants with low amyloid burden. These reductions were also observed when amyloid burden was treated as a continuous, rather than a dichotomous, measure and when controlling for age and structural atrophy. Whole-brain analyses initiated by seeding the posterior cingulate cortex, a region of high amyloid burden in Alzheimer's disease, revealed significant disruption in the default network including functional disconnection of the hippocampal formation.

Span, CRUNCH, and beyond: Working memory capacity and the aging brain

Article

Full-text available

Apr 2009
J COGNITIVE NEUROSCI

Neuroimaging data emphasize that older adults often show greater extent of brain activation than younger adults for similar objective levels of difficulty. A possible interpretation of this finding is that older adults need to recruit neuronal resources at lower loads than younger adults, leaving no resources for higher loads, and thus leading to performance decrements [Compensation-Related Utilization of Neural Circuits Hypothesis; e.g., Reuter-Lorenz, P. A., & Cappell, K. A. Neurocognitive aging and the compensation hypothesis. Current Directions in Psychological Science, 17, 177-182, 2008]. The Compensation-Related Utilization of Neural Circuits Hypothesis leads to the prediction that activation differences between younger and older adults should disappear when task difficulty is made subjectively comparable. In a Sternberg memory search task, this can be achieved by assessing brain activity as a function of load relative to the individual's memory span, which declines with age. Specifically, we hypothesized a nonlinear relationship between load and both performance and brain activity and predicted that asymptotes in the brain activation function should correlate with performance asymptotes (corresponding to working memory span). The results suggest that age differences in brain activation can be largely attributed to individual variations in working memory span. Interestingly, the brain activation data show a sigmoid relationship with load. Results are discussed in terms of Cowan's [Cowan, N. The magical number 4 in short-term memory: A reconsideration of mental storage capacity. Behavioral and Brain Sciences, 24, 87-114, 2001] model of working memory and theories of impaired inhibitory processes in aging.

SRF and myocardin regulate LRP-mediated amyloid-β clearance in brain vascular cells

Article

Full-text available

Feb 2009
NAT CELL BIOL

Amyloid beta-peptide (Abeta) deposition in cerebral vessels contributes to cerebral amyloid angiopathy (CAA) in Alzheimer's disease (AD). Here, we report that in AD patients and two mouse models of AD, overexpression of serum response factor (SRF) and myocardin (MYOCD) in cerebral vascular smooth muscle cells (VSMCs) generates an Abeta non-clearing VSMC phenotype through transactivation of sterol regulatory element binding protein-2, which downregulates low density lipoprotein receptor-related protein-1, a key Abeta clearance receptor. Hypoxia stimulated SRF/MYOCD expression in human cerebral VSMCs and in animal models of AD. We suggest that SRF and MYOCD function as a transcriptional switch, controlling Abeta cerebrovascular clearance and progression of AD.

The Adaptive Brain: Aging and Neurocognitive Scaffolding

Article

Full-text available

Feb 2009

There are declines with age in speed of processing, working memory, inhibitory function, and long-term memory, as well as decreases in brain structure size and white matter integrity. In the face of these decreases, functional imaging studies have demonstrated, somewhat surprisingly, reliable increases in prefrontal activation. To account for these joint phenomena, we propose the scaffolding theory of aging and cognition (STAC). STAC provides an integrative view of the aging mind, suggesting that pervasive increased frontal activation with age is a marker of an adaptive brain that engages in compensatory scaffolding in response to the challenges posed by declining neural structures and function. Scaffolding is a normal process present across the lifespan that involves use and development of complementary, alternative neural circuits to achieve a particular cognitive goal. Scaffolding is protective of cognitive function in the aging brain, and available evidence suggests that the ability to use this mechanism is strengthened by cognitive engagement, exercise, and low levels of default network engagement.

Evidence for task-dependent memory dysfunction in the aged monkey

Article

Full-text available

Nov 1989

Experimentally naive adult (9-11 years old) and aged (approximately 22-26 years old) female rhesus monkeys were evaluated on 3 neuropsychological tests of memory function. Aged monkeys were impaired in a delayed response test of visuospatial memory when the retention interval of the task was increased from 0 to 10 sec. These animals performed as well as younger subjects, however, at very short delays (0 and 1 sec), when the memory demands of the task were minimal. The same subjects were then trained in a delayed nonmatching to sample (DNMS) test of visual object recognition memory. Although they required significantly more training than the younger subjects to learn the nonmatching principle of the task, aged animals were only minimally impaired when recognition memory was tested at retention intervals ranging from 10 sec to 22 hr. In contrast to their relatively intact performance on the object recognition task, aged monkeys were dramatically impaired in a second version of DNMS that required subjects to remember the temporal order in which objects were presented. These findings support the view that certain memory functions are differentially susceptible to age-dependent deterioration. Since neuropsychological studies in young subjects demonstrate that different brain regions make relatively specific contributions to learning and memory, the task-dependent deficits observed in the aged monkey are important for determining which neural structures mediate age-dependent cognitive dysfunction. According to this perspective, aged monkeys were impaired on tasks known to be sensitive to prefrontal cortical damage, but the same animals performed well on a DNMS procedure that subjects with medial temporal lobe damage fail. These results suggest that prefrontal cortical dysfunction may mediate prominent aspects of age-dependent cognitive impairment in the monkey.

An application of prefrontal cortex theory to cognitive aging

Article

Full-text available

Oct 1996

Robert West

The purpose of this review is to extend the existing application of the frontal lobe hypothesis of cognitive aging beyond the limited work on inhibitory control (F. N. Dempster, 1992) to include memory processes supported by the prefrontal cortex. To establish a background for this analysis, I review existing models of prefrontal cortex function and present a synthesized model that includes a general function of temporal integration, supported by 4 specific processes: prospective memory, retrospective memory, interference control, and inhibition of prepotent responses. I found the frontal lobe hypothesis to perform well, with the exception of an inability to account for age-related declines in item recall and recognition memory, possibly a result of age-related declines in medial temporal function.

Article

Full-text available

Feb 1997

Positron emission tomography (PET) was used to compare regional cerebral blood flow (rCBF) in young (mean 26 years) and old (mean 70 years) subjects while they were encoding, recognizing, and recalling word pairs. A multivariate partial-least-squares (PLS) analysis of the data was used to identify age-related neural changes associated with (1) encoding versus retrieval and (2) recognition versus recall. Young subjects showed higher activation than old subjects (1) in left prefrontal and occipito-temporal regions during encoding and (2) in right prefrontal and parietal regions during retrieval. Old subjects showed relatively higher activation than young subjects in several regions, including insular regions during encoding, cuneus/precuneus regions during recognition, and left prefrontal regions during recall. Frontal activity in young subjects was left-lateralized during encoding and right-lateralized during recall [hemispheric encoding/retrieval asymmetry (HERA)], whereas old adults showed little frontal activity during encoding and a more bilateral pattern of frontal activation during retrieval. In young subjects, activation in recall was higher than that in recognition in cerebellar and cingulate regions, whereas recognition showed higher activity in right temporal and parietal regions. In old subjects, the differences in blood flow between recall and recognition were smaller in these regions, yet more pronounced in other regions. Taken together, the results indicate that advanced age is associated with neural changes in the brain systems underlying encoding, recognition, and recall. These changes take two forms: (1) age-related decreases in local regional activity, which may signal less efficient processing by the old, and (2) age-related increases in activity, which may signal functional compensation.

Selective aging of the human cerebral cortex observed in Vivo: Differential vulnerability of the prefrontal gray matter

Article

Full-text available

Aug 1997

In a prospective cross-sectional study, we used computerized volumetry of magnetic resonance images to examine the patterns of brain aging in 148 healthy volunteers. The most substantial age-related decline was found in the volume of the prefrontal gray matter. Smaller age-related differences were observed in the volume of the fusiform, inferior temporal and superior parietal cortices. The effects of age on the hippocampal formation, the postcentral gyrus, prefrontal white matter and superior parietal white matter were even weaker. No significant age-related differences were observed in the parahippocampal and anterior cingulate gyri, inferior parietal lobule, pericalcarine gray matter, the precentral gray and white matter, postcentral white matter and inferior parietal white matter. The volume of the total brain volume and the hippocampal formation was larger in men than in women even after adjustment for height. Inferior temporal cortex showed steeper aging trend in men. Small but consistent rightward asymmetry was found in the whole cerebral hemispheres, superior parietal, fusiform and orbito-frontal cortices, postcentral and prefrontal white matter. The left side was larger than the right in the dorsolateral prefrontal, parahippocampal, inferior parietal and pericalcarine cortices, and in the parietal white matter. However, there were no significant differences in age trends between the hemispheres.

H. Morrison, J. H. & Hof, P. R. Life and death of neurons in the aging brain. Science 278, 412-419

Article

Full-text available

Nov 1997

Neurodegenerative disorders are characterized by extensive neuron death that leads to functional decline, but the neurobiological correlates of functional decline in normal aging are less well defined. For decades, it has been a commonly held notion that widespread neuron death in the neocortex and hippocampus is an inevitable concomitant of brain aging, but recent quantitative studies suggest that neuron death is restricted in normal aging and unlikely to account for age-related impairment of neocortical and hippocampal functions. In this article, the qualitative and quantitative differences between aging and Alzheimer's disease with respect to neuron loss are discussed, and age-related changes in functional and biochemical attributes of hippocampal circuits that might mediate functional decline in the absence of neuron death are explored. When these data are viewed comprehensively, it appears that the primary neurobiological substrates for functional impairment in aging differ in important ways from those in neurodegenerative disorders such as Alzheimer's disease.

Age Differences in the Frontal Lateralization of Verbal and Spatial Working Memory Revealed by PET

Article

Full-text available

Feb 2000

Age-related decline in working memory figures prominently in theories of cognitive aging. However, the effects of aging on the neural substrate of working memory are largely unknown. Positron emission tomography (PET) was used to investigate verbal and spatial short-term storage (3 sec) in older and younger adults. Previous investigations with younger subjects performing these same tasks have revealed asymmetries in the lateral organization of verbal and spatial working memory. Using volume of interest (VOI) analyses that specifically compared activation at sites identified with working memory to their homologous twin in the opposite hemisphere, we show pronounced age differences in this organization, particularly in the frontal lobes: In younger adults, activation is predominantly left lateralized for verbal working memory, and right lateralized for spatial working memory, whereas older adults show a global pattern of anterior bilateral activation for both types of memory. Analyses of frontal subregions indicate that several underlying patterns contribute to global bilaterality in older adults: most notably, bilateral activation in areas associated with rehearsal, and paradoxical laterality in dorsolateral prefrontal sites (DLPFC; greater left activation for spatial and greater right activation for verbal). We consider several mechanisms that could account for these age differences including the possibility that bilateral activation reflects recruitment to compensate for neural decline.

Clearance of Alzheimer's amyloid-??1-40 peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier

Article

Full-text available

Dec 2000

Elimination of amyloid-ss peptide (Ass) from the brain is poorly understood. After intracerebral microinjections in young mice, (125)I-Ass(1-40) was rapidly removed from the brain (t(1/2) </= 25 minutes), mainly by vascular transport across the blood-brain barrier (BBB). The efflux transport system for Ass(1-40) at the BBB was half saturated at 15.3 nM, and the maximal transport capacity was reached between 70 nM and 100 nM. Ass(1-40) clearance was substantially inhibited by the receptor-associated protein, and by antibodies against LDL receptor-related protein-1 (LRP-1) and alpha(2)-macroglobulin (alpha(2)M). As compared to adult wild-type mice, clearance was significantly reduced in young and old apolipoprotein E (apoE) knockout mice, and in old wild-type mice. There was no evidence that Ass was metabolized in brain interstitial fluid and degraded to smaller peptide fragments and amino acids before its transport across the BBB into the circulation. LRP-1, although abundant in brain microvessels in young mice, was downregulated in older animals, and this downregulation correlated with regional Ass accumulation in brains of Alzheimer's disease (AD) patients. We conclude that the BBB removes Ass from the brain largely via age-dependent, LRP-1-mediated transport that is influenced by alpha(2)M and/or apoE, and may be impaired in AD.

Hemispheric asymmetry reduction in older adults: The HAROLD model.

Article

Full-text available

Apr 2002

Roberto Cabeza

A model of the effects of aging on brain activity during cognitive performance is introduced. The model is called HAROLD (hemispheric asymmetry reduction in older adults), and it states that, under similar circumstances, prefrontal activity during cognitive performances tends to be less lateralized in older adults than in younger adults. The model is supported by functional neuroimaging and other evidence in the domains of episodic memory, semantic memory, working memory, perception, and inhibitory control. Age-related hemispheric asymmetry reductions may have a compensatory function or they may reflect a dedifferentiation process. They may have a cognitive or neural origin, and they may reflect regional or network mechanisms. The HAROLD model is a cognitive neuroscience model that integrates ideas and findings from psychology and neuroscience of aging.

The prefrontal cortex: Categories, concepts and cognition

Article

Full-text available

Sep 2002

The ability to generalize behaviour-guiding principles and concepts from experience is key to intelligent, goal-directed behaviour. It allows us to deal efficiently with a complex world and to adapt readily to novel situations. We review evidence that the prefrontal cortex-the cortical area that reaches its greatest elaboration in primates-plays a central part in acquiring and representing this information. The prefrontal cortex receives highly processed information from all major forebrain systems, and neurophysiological studies suggest that it synthesizes this into representations of learned task contingencies, concepts and task rules. In short, the prefrontal cortex seems to underlie our internal representations of the 'rules of the game'. This may provide the necessary foundation for the complex behaviour of primates, in whom this structure is most elaborate.

Diffusion tensor MRI correlates with executive dysfunction in patients with ischaemic leukoaraiosis

Article

Full-text available

Apr 2004

Cerebral small vessel disease is a common cause of vascular dementia. Both discrete lacunar infarcts and more diffuse ischaemic changes, seen as confluent high signal (leukoaraiosis) on T2 weighted magnetic resonance imaging (MRI), occur. However, there is a weak correlation between T2 lesion load and cognitive impairment. Diffusion tensor MRI (DTI) is a new technique that may provide a better index of white matter damage. To determine whether DTI measures are correlated more strongly with cognitive performance than lesion load on T2 weighted images, and whether these correlations are independent of conventional MRI parameters. 36 patients with ischaemic leukoaraiosis (leukoaraiosis plus a previous lacunar stroke) and 19 healthy volunteers underwent DTI, conventional MRI, and neuropsychological assessment. On DTI, diffusivity was increased both within lesions and in normal appearing white matter. Mean diffusivity of normal appearing white matter correlated with full scale IQ (r = -0.46, p = 0.009) and tests of executive function. These correlations remained significant after controlling for age, sex, brain volume, and T1/T2 lesion volumes. No significant correlation was identified between T2 lesion load and IQ or neuropsychological scores. Of conventional measures, brain volume correlated best with cognitive function. Diffusion tensor measurements correlate better with cognition than conventional MRI measures. They may be useful in monitoring disease progression and as a surrogate marker for treatment trials. The findings support the role of white matter damage and disruption of white matter connections in the pathogenesis of cognitive impairment in cerebral small vessel disease.

White Matter Changes Compromise Prefrontal Cortex Function in Healthy Elderly Individuals

Article

Full-text available

Apr 2006

Changes in memory function in elderly individuals are often attributed to dysfunction of the prefrontal cortex (PFC). One mechanism for this dysfunction may be disruption of white matter tracts that connect the PFC with its anatomical targets. Here, we tested the hypothesis that white matter degeneration is associated with reduced prefrontal activation. We used white matter hyperintensities (WMH), a magnetic resonance imaging (MRI) finding associated with cerebrovascular disease in elderly individuals, as a marker for white matter degeneration. Specifically, we used structural MRI to quantify the extent of WMH in a group of cognitively normal elderly individuals and tested whether these measures were predictive of the magnitude of prefrontal activity (fMRI) observed during performance of an episodic retrieval task and a verbal working memory task. We also examined the effects of WMH located in the dorsolateral frontal regions with the hypothesis that dorsal PFC WMH would be strongly associated with not only PFC function, but also with areas that are anatomically and functionally linked to the PFC in a task-dependent manner. Results showed that increases in both global and regional dorsal PFC WMH volume were associated with decreases in PFC activity. In addition, dorsal PFC WMH volume was associated with decreased activity in medial temporal and anterior cingulate regions during episodic retrieval and decreased activity in the posterior parietal and anterior cingulate cortex during working memory performance. These results suggest that disruption of white matter tracts, especially within the PFC, may be a mechanism for age-related changes in memory functioning.

Cyclic Estrogen Replacement Improves Cognitive Function in Aged Ovariectomized Rhesus Monkeys

Article

Full-text available

Aug 2003
J NEUROSCI

Among the identified risks and benefits of hormone-replacement therapy, the effects of treatment on cognitive function in postmenopausal women have proved difficult to define. Here we conducted a controlled, prospective analysis in a nonhuman primate model to test whether surgical menopause and estrogen replacement influence the cognitive outcome of normal aging. Sixteen aged rhesus monkeys were ovariectomized, and throughout the course of subsequent neuropsychological assessment, half received a regimen of low-dose, cyclic estradiol replacement. Hormone treatment substantially reversed the marked age-related impairment vehicle-injected monkeys exhibited on a delayed response test of spatial working memory. Modest improvement was also observed on a delayed nonmatching-to-sample recognition memory task. In contrast, ovariectomy exacerbated age-related deficits in object discrimination learning; the magnitude of this effect was equivalent among vehicle- and estrogen-treated monkeys. Together, these results demonstrate that ovarian hormone status can broadly influence normal cognitive aging in monkeys, affecting capacities mediated by multiple brain regions, including the prefrontal cortex and the medial temporal lobe memory system. The animal model established here should enable progress toward defining the neurobiological mechanisms that mediate the beneficial effects of estrogen on age-related cognitive decline in primates.

Interactive effects of age and estrogen on cognition and pyramidal neurons in monkey prefrontal cortex

Article

Full-text available

Aug 2007

We previously reported that long-term cyclic estrogen (E) treatment reverses age-related impairment of cognitive function mediated by the dorsolateral prefrontal cortex (dlPFC) in ovariectomized (OVX) female rhesus monkeys, and that E induces a corresponding increase in spine density in layer III dlPFC pyramidal neurons. We have now investigated the effects of the same E treatment in young adult females. In contrast to the results for aged monkeys, E treatment failed to enhance dlPFC-dependent task performance relative to vehicle control values (group young OVX+Veh) but nonetheless led to a robust increase in spine density. This response was accompanied by a decline in dendritic length, however, such that the total number of spines per neuron was equivalent in young OVX+Veh and OVX+E groups. Robust effects of chronological age, independent of ovarian hormone status, were also observed, comprising significant age-related declines in dendritic length and spine density, with a preferential decrease in small spines in the aged groups. Notably, the spine effects were partially reversed by cyclic E administration, although young OVX+Veh monkeys still had a higher complement of small spines than did aged E treated monkeys. In summary, layer III pyramidal neurons in the dlPFC are sensitive to ovarian hormone status in both young and aged monkeys, but these effects are not entirely equivalent across age groups. The results also suggest that the cognitive benefit of E treatment in aged monkeys is mediated by enabling synaptic plasticity through a cyclical increase in small, highly plastic dendritic spines in the primate dlPFC. • aging • estradiol • hormone • neocortex • plasticity

Article

Full-text available

Mar 2008
P NATL ACAD SCI USA

The neural underpinnings of age-related memory impairment remain to be fully elucidated. Using a subsequent memory face–name functional MRI (fMRI) paradigm, young and old adults showed a similar magnitude and extent of hippocampal activation during successful associative encoding. Young adults demonstrated greater deactivation (task-induced decrease in BOLD signal) in medial parietal regions during successful compared with failed encoding, whereas old adults as a group did not demonstrate a differential pattern of deactivation between trial types. The failure of deactivation was particularly evident in old adults who performed poorly on the memory task. These low-performing old adults demonstrated greater hippocampal and prefrontal activation to achieve successful encoding trials, possibly as a compensatory response. Findings suggest that successful encoding requires the coordination of neural activity in hippocampal, prefrontal, and parietal regions, and that age-related memory impairment may be primarily related to a loss of deactivation in medial parietal regions. • aging • fMRI • hippocampus • default network • Alzheimer's disease

Life and death of neurons in the aging brain

Article

Jul 1999
Recherche

Diffusion tensor MRI correlates with executive dysfunction in patients with ischaemic leukoaraiosis

Article

Mar 2004

M O'Sullivan

Background: Cerebral small vessel disease is a common cause of vascular dementia. Both discrete lacunar infarcts and more diffuse ischaemic changes, seen as confluent high signal (leukoaraiosis) on T2 weighted magnetic resonance imaging (MRI), occur. However, there is a weak correlation between T2 lesion load and cognitive impairment. Diffusion tensor MRI (DTI) is a new technique that may provide a better index of white matter damage. Objectives: To determine whether DTI measures are correlated more strongly with cognitive performance than lesion load on T2 weighted images, and whether these correlations are independent of conventional MRI parameters. Methods: 36 patients with ischaemic leukoaraiosis (leukoaraiosis plus a previous lacunar stroke) and 19 healthy volunteers underwent DTI, conventional MRI, and neuropsychological assessment. Results: On DTI, diffusivity was increased both within lesions and in normal appearing white matter. Mean diffusivity of normal appearing white matter correlated with full scale IQ (r = −0.46, p = 0.009) and tests of executive function. These correlations remained significant after controlling for age, sex, brain volume, and T1/T2 lesion volumes. No significant correlation was identified between T2 lesion load and IQ or neuropsychological scores. Of conventional measures, brain volume correlated best with cognitive function. Conclusions: Diffusion tensor measurements correlate better with cognition than conventional MRI measures. They may be useful in monitoring disease progression and as a surrogate marker for treatment trials. The findings support the role of white matter damage and disruption of white matter connections in the pathogenesis of cognitive impairment in cerebral small vessel disease.

Neural Recruitment and CognitiveAging: Two Hemispheres Are Better Than One, Especially as You Age

Article

Nov 1999

Several neuroimaging studies have reported that older adults show weaker activations in some brain areas together with stronger activations in other areas, compared with younger adults performing the same task. This pattern may reflect neural recruitment that compensates for age-related neural declines. The recruitment hypothesis was tested in a visual laterality study that investigated age differences in the efficiency of bihemispheric processing. Letter-matching tasks of varying complexity were performed under two conditions: (a) matching letters projected to the same visual field (hemisphere) and (b) matching letters projected to opposite visual fields (hemispheres). As predicted by the recruitment hypothesis, older adults generally performed better in the bilateral than unilateral condition, whereas younger adults showed this pattern onlyfor the most complex task. We discuss the relation between these results and neuroimaging evidence for recruitment, and the relevance of the present bihemispheric advantage to other evidence for age-related changes in interhemispheric transfer.

Dissociation of Object and Spatial Vision in Human Extrastriate Cortex: Age-Related Changes in Activation of Regional Cerebral Blood Flow Measured with [15 O]Water and Positron Emission Tomography

Article

Jan 1992
J COGNITIVE NEUROSCI

We previously reported selective activation of regional cerebral blood flow (rCBF) in occipitotemporal cortex during a face matching task (object vision) and activation in superior parietal cortex during a dot-location matching task (spatial vision) in young subjects, The purpose of the present study was to determine the effects of aging on these extrastriate visual processing systems. Eleven young (mean age 27 4 years) and nine old (mean age 72 7 years) male subjects were studied. Positron emission tomographic scans were performed using a Scanditronix PC10247B tomograph and H215O to measure rCBF. To locate brain areas that were activated by the visual tasks, pixel-by-pixel difference images were computed between images from a control task and images from the face and dot-location matching tasks. Both young and old subjects showed rCBF activation during face matching primarily in occipitotemporal cortex, and activation of superior parietal cortex during dot-location matching. Statistical comparisons of these activations showed that the old subjects had more activation of occipitotemporal cortex during the spatial task and more activation of superior parietal cortex during the object task than did the young subjects. These results show less functional separation of the dorsal and ventral visual pathways in older subjects, and may reflect an age-related reduction in the processing efficiency of these visual cortical areas.

Memory and Aging

Article

Dec 1996

Leah Light

examines 4 accounts of the nature of memory impairment in old age / these range from the view that poorer memory in old age arises from inefficient encoding and/or retrieval strategies that are subject to remediation by appropriate interventions to less optimistic views that declining memory is the result of irreversible age-related changes in basic mechanisms underlying cognition, such as reductions in working memory capacity, reduced processing speed, and impaired inhibition / the 4 classes of hypotheses considered are that age-related decrements in memory are attributable to (1) failures of strategic processing, (2) deficits in semantic processing, (3) problems in the utilization of context, and (4) changes in basic mechanisms underlying all aspects of cognition (PsycINFO Database Record (c) 2012 APA, all rights reserved)

Vascular health and longitudinal changes in brain and cognition in middle-aged and older adults

Article

Mar 2007

The impact of vascular health on the relations between structural brain changes and cognition was assessed in a longitudinal study of 46 adults, 23 of whom remained healthy for 5 years and 23 of whom had hypertension at baseline or acquired vascular problems during follow-up. At both measurement occasions, the volume of white matter hyperintensities (WMH) and regional brain volumes correlated with age. In 5 years, WMH volume more than doubled in the vascular risk group but did not increase in healthy participants. The frontal lobes had the highest WMH load at baseline and follow-up; the parietal WMH showed the greatest rate of expansion. In the vascular risk group, systolic blood pressure at follow-up correlated with posterior WMH volume. The fastest cortical shrinkage was observed in the prefrontal cortex and the hippocampus. Fluid intelligence correlated with WMH burden and declined along with faster WMH progression. In the vascular risk group, WMH progression and shrinkage of the fusiform cortex correlated with decline in working memory. Thus, poor vascular health contributes to age-related declines in brain and cognition, and some of the age-related declines may be limited to persons with elevated vascular risk.

Late life cognitive control deficits are accentuated by white matter disease burden

Article

Jun 2011
BRAIN

Recent evidence suggests that age-related impairments in cognition may be mediated by a specific deficit in the ability to maintain goal-relevant information, a critical component of cognitive control dependent on the dorsolateral prefrontal cortex, although the underlying neural mechanism of these deficits remains unclear. To examine white matter hyperintensities as a neurobiological mechanism of these impairments, older individuals with severe white matter hyperintensity burden, older individuals with low white matter hyperintensity burden, and young adults were assessed in an event-related functional imaging scan while performing the 'AX'-continuous performance task. Individuals with severe white matter hyperintensity burden showed a significant reduction in dorsolateral prefrontal cortex activity during the high cognitive control cue condition relative to the low white matter hyperintensity group and young individuals. Conversely, those with severe white matter hyperintensity burden showed greater activity in rostral anterior cingulate cortex compared to young individuals. These results are consistent with impaired cognitive control and a possible failure to deactivate default-mode regions in these subjects. Additionally, those with severe white matter hyperintensity burden showed reduced functional connectivity between dorsolateral prefrontal cortex and task-relevant brain regions including middle frontal gyrus, and supramarginal gyrus relative to young subjects and those with minimal white matter hyperintensity burden. These results suggest that age-related goal maintenance impairments and associated dorsolateral prefrontal cortex dysfunction may partly reflect incipient white matter disease of interconnected cognitive networks.

Age and amyloid-related alterations in default network habituation to stimulus repetition

Article

Feb 2011

The neural networks supporting encoding of new information are thought to decline with age, although mnemonic techniques such as repetition may enhance performance in older individuals. Accumulation of amyloid-β, one hallmark pathology of Alzheimer's disease (AD), may contribute to functional alterations in memory networks measured with functional magnetic resonance imaging (fMRI) prior to onset of cognitive impairment. We investigated the effects of age and amyloid burden on fMRI activity in the default network and hippocampus during repetitive encoding. Older individuals, particularly those with high amyloid burden, demonstrated decreased task-induced deactivation in the posteromedial cortices during initial stimulus presentation and failed to modulate fMRI activity in response to repeated trials, whereas young subjects demonstrated a stepwise decrease in deactivation with repetition. The hippocampus demonstrated similar patterns across the groups, showing task-induced activity that decreased in response to repetition. These findings demonstrate that age and amyloid have dissociable functional effects on specific nodes within a distributed memory network, and suggest that functional brain changes may begin far in advance of symptomatic Alzheimer's disease.

Synaptic correlates of memory and menopause in the hippocampal dentate gyrus in rhesus monkeys

Article

Oct 2010

Aged rhesus monkeys exhibit deficits in hippocampus-dependent memory, similar to aging humans. Here we explored the basis of cognitive decline by first testing young adult and aged monkeys on a standard recognition memory test (delayed nonmatching-to-sample test; DNMS). Next we quantified synaptic density and morphology in the hippocampal dentate gyrus (DG) outer (OML) and inner molecular layer (IML). Consistent with previous findings, aged monkeys were slow to learn DNMS initially, and they performed significantly worse than young subjects when challenged with longer retention intervals. Although OML and IML synaptic parameters failed to differ across the young and aged groups, the density of perforated synapses in the OML was coupled with recognition memory accuracy. Independent of chronological age, monkeys classified on the basis of menses data as peri- or post-menopausal scored worse on DNMS, and displayed lower OML perforated synapse density, than premenopausal monkeys. These results suggest that naturally occurring reproductive senescence potently influences synaptic connectivity in the DG OML, contributing to individual differences in the course of normal cognitive aging.

Patterns Of Altered Cortical Perfusion And Diminished Subcortical Integrity In Posttraumatic Stress Disorder: A MRI Study

Article

Jan 2011
NEUROIMAGE

Posttraumatic stress disorder (PTSD) accounts for a substantial proportion of casualties among surviving soldiers of the Iraq and Afghanistan wars. Currently, the assessment of PTSD is based exclusively on symptoms, making it difficult to obtain an accurate diagnosis. This study aimed to find potential imaging markers for PTSD using structural, perfusion, and diffusion magnetic resonance imaging (MRI) together. Seventeen male veterans with PTSD (45 ± 14 years old) and 15 age-matched male veterans without PTSD had measurements of regional cerebral blood flow (rCBF) using arterial spin labeling (ASL) perfusion MRI. A slightly larger group had also measurements of white matter integrity using diffusion tensor imaging (DTI) with computations of regional fractional anisotropy (FA). The same subjects also had structural MRI of the hippocampal subfields as reported recently (W. Zhen et al. Arch Gen Psych 2010;67(3):296-303). On ASL-MRI, subjects with PTSD had increased rCBF in primarily right parietal and superior temporal cortices. On DTI, subjects with PTSD had FA reduction in white matter regions of the prefrontal lobe, including areas near the anterior cingulate cortex and prefrontal cortex as well as in the posterior angular gyrus. In conclusion, PTSD is associated with a systematic pattern of physiological and structural abnormalities in predominantly frontal lobe and limbic brain regions. Structural, perfusion, and diffusion MRI together may provide a signature for a PTSD marker.

Malignant Astrocytomas A System Disease

Article

Mar 2010

Hassan M Fathallah-Shaykh

JAMA A Network Model of a Cooperative Genetic Landscape in Brain Tumors Markus Bredel, MD, PhD; Denise M. Scholtens, PhD; Griffith R. Harsh, MD; Claudia Bredel, PhD; James P. Chandler, MD; Jaclyn J. Renfrow, MA; Ajay K. Yadav, PhD; Hannes Vogel, MD, PhD; Adrienne C. Scheck, PhD; Robert Tibshirani, PhD; Branimir I. Sikic, MD Context: Gliomas, particularly glioblastomas, are among the deadliest of human tumors. Gliomas emerge through the accumulation of recurrent chromosomal alterations, some of which target yet-to-be-discovered cancer genes. A persistent question concerns the biological basis for the coselection of these alterations during gliomagenesis. Objectives: To describe a network model of a cooperative genetic landscape in gliomas and to evaluate its clinical relevance. Design, Setting, and Patients: Multidimensional genomic profiles and clinical profiles of 501 patients with gliomas (45 tumors in an initial discovery set collected between 2001 and 2004 and 456 tumors in validation sets made public between 2006 and 2008) from multiple academic centers in the United States and The Cancer Genome Atlas Pilot Project (TCGA). Main Outcome Measures: Identification of genes with coincident genetic alterations, correlated gene dosage and gene expression, and multiple functional interactions; association between those genes and patient survival. Results: Gliomas select for a nonrandom genetic landscape—a consistent pattern of chromosomal alterations—that involves altered regions (“territories”) on chromosomes 1p, 7, 8q, 9p, 10, 12q, 13q, 19q, 20, and 22q (false-discovery rate-corrected P < .05). A network model shows that these territories harbor genes with putative synergistic, tumor-promoting relationships. The coalteration of the most interactive of these genes in glioblastoma is associated with unfavorable patient survival. A multigene risk scoring model based on 7 landscape genes (POLD2, CYCS, MYC, AKR1C3, YME1L1, ANXA7, and PDCD4) is associated with the duration of overall survival in 189 glioblastoma samples from TCGA (global log-rank P = .02 comparing 3 survival curves for patients with 0-2, 3-4, and 5-7 dosage-altered genes). Groups of patients with 0 to 2 (low-risk group) and 5 to 7 (high-risk group) dosage-altered genes experienced 49.24 and 79.56 deaths per 100 person-years (hazard ratio [HR], 1.63; 95% confidence interval [CI], 1.10-2.40; Cox regression model P = .02), respectively. These associations with survival are validated using gene expression data in 3 independent glioma studies, comprising 76 (global log-rank P = .003; 47.89 vs 15.13 deaths per 100 person-years for high risk vs low risk; Cox model HR, 3.04; 95% CI, 1.49-6.20; P = .002) and 70 (global log-rank P = .008; 83.43 vs 16.14 deaths per 100 person-years for high risk vs low risk; HR, 3.86; 95% CI, 1.59-9.35; P = .003) high-grade gliomas and 191 glioblastomas (global log-rank P = .002; 83.23 vs 34.16 deaths per 100 person-years for high risk vs low risk; HR, 2.27; 95% CI, 1.44-3.58; P < .001). Conclusions: The alteration of multiple networking genes by recurrent chromosomal aberrations in gliomas deregulates critical signaling pathways through multiple, cooperative mechanisms. These mutations, which are likely due to nonrandom selection of a distinct genetic landscape during gliomagenesis, are associated with patient prognosis. JAMA. 2009;302(3):261-275..

Structral dynamics of dendritic spines in memory and cognition

Article

Feb 2010

Recent studies show that dendritic spines are dynamic structures. Their rapid creation, destruction and shape-changing are essential for short- and long-term plasticity at excitatory synapses on pyramidal neurons in the cerebral cortex. The onset of long-term potentiation, spine-volume growth and an increase in receptor trafficking are coincident, enabling a 'functional readout' of spine structure that links the age, size, strength and lifetime of a synapse. Spine dynamics are also implicated in long-term memory and cognition: intrinsic fluctuations in volume can explain synapse maintenance over long periods, and rapid, activity-triggered plasticity can relate directly to cognitive processes. Thus, spine dynamics are cellular phenomena with important implications for cognition and memory. Furthermore, impaired spine dynamics can cause psychiatric and neurodevelopmental disorders.

Amyloid Deposition Is Associated with Impaired Default Network Function in Older Persons without Dementia

Article

Aug 2009

Alzheimer's disease (AD) has been associated with functional alterations in a distributed network of brain regions linked to memory function, with a recent focus on the cortical regions collectively known as the default network. Posterior components of the default network, including the precuneus and posterior cingulate, are particularly vulnerable to early deposition of amyloid beta-protein, one of the hallmark pathologies of AD. In this study, we use in vivo amyloid imaging to demonstrate that high levels of amyloid deposition are associated with aberrant default network functional magnetic resonance imaging (fMRI) activity in asymptomatic and minimally impaired older individuals, similar to the pattern of dysfunction reported in AD patients. These findings suggest that amyloid pathology is linked to neural dysfunction in brain regions supporting memory function and provide support for the hypothesis that cognitively intact older individuals with evidence of amyloid pathology may be in early stages of AD.

Context processing in older adults: Evidence for a theory relating cognitive control to neurobiology in healthy aging

Article

Jan 2002

A theory of cognitive aging is presented in which healthy older adults are hypothesized to suffer from disturbances in the processing of context that impair cognitive control function across multiple domains, including attention, inhibition, and working memory. These cognitive disturbances are postulated to be directly related to age-related decline in the function of the dopamine (DA) system in the prefrontal cortex (PFC). A connectionist computational model is described that implements specific mechanisms for the role of DA and PFC in context processing. The behavioral predictions of the model were tested in a large sample of older (N = 81) and young (N = 175) adults performing variants of a simple cognitive control task that placed differential demands on context processing. Older adults exhibited both performance decrements and, counterintuitively, performance improvements that are in close agreement with model predictions.

White matter lesions impair frontal lobe function regardless of their location

Article

Aug 2004
NEUROLOGY

To analyze the effect of white matter lesions in different brain regions on regional cortical glucose metabolism, regional cortical atrophy, and cognitive function in a sample with a broad range of cerebrovascular disease and cognitive function. Subjects (n = 78) were recruited for a study of subcortical ischemic vascular disease (SIVD) and Alzheimer disease (AD) contributions to dementia. A new method was developed to define volumes of interest from high-resolution three-dimensional T1-weighted MR images. Volumetric measures of MRI segmented white matter signal hyperintensities (WMH) in five different brain regions were related to regional PET glucose metabolism (rCMRglc) in cerebral cortex, MRI measures of regional cortical atrophy, and neuropsychological assessment of executive and memory function. WMH was significantly higher in the prefrontal region compared to the other brain regions. In all subjects, higher frontal and parietal WMH were associated with reduced frontal rCMRglc, whereas occipitotemporal WMH was only marginally associated with frontal rCMRglc. These associations were stronger and more widely distributed in nondemented subjects where reduced frontal rCMRglc was correlated with WMH for all regions measured. In contrast, there was no relationship between WMH in any brain region and rCMRglc in either parietal or occipitotemporal regions. WMHs in all brain regions were associated with low executive scores in nondemented subjects. The frontal lobes are most severely affected by SIVD. WMHs are more abundant in the frontal region. Regardless of where in the brain these WMHs are located, they are associated with frontal hypometabolism and executive dysfunction.

Modulation of Cortisol Metabolism during Treatment of Acromegaly Is Independent of Body Composition and Insulin Sensitivity

Article

Apr 2004

The set point of cortisol-cortisone conversion is shifted in the direction of cortisone by the inhibition of the activity of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) during adult GH replacement and in active acromegaly. Additionally, both fat mass and insulin may modulate 11beta-HSD1 and are both influenced by changes in GH status. This study examined the relative direct contribution of GH/IGF1 in modulating cortisol metabolism. Overall cortisol/cortisone conversion (ratio of urine 11-hydroxy-/11-oxo-cortisol metabolites; Fm/Em), insulin sensitivity (homeostatic model assessment; HOMA %S) and fat mass (DXA) were examined in parallel in 6 patients (mean age 53 years, range 42-76; 4 males, 2 females) with previously untreated active acromegaly during 6 months of therapy with Sandostatin LAR (20-30 mg i.m. 4 weekly). All but 1 patient had normal ACTH reserve. At baseline, Pearson correlation demonstrated an inverse relationship between serum GH (mean of a 5-point day curve) and Fm/Em (r = -0.83, p = 0.04) and a trend towards an inverse relationship between HOMA %S and Fm/Em (r = -0.79, p = 0.06) but no other patterns were evident. During the course of treatment, serum GH decreased from 9.9 +/- 6.4 (mean +/- SD) to 3.5 +/- 3.1 ng/ml (p < 0.01) and serum IGF-1 from 785 +/- 268 to 431 +/- 156 ng/ml (p < 0.005). Fm/Em increased from 0.52 +/- 0.1 to 0.75 +/- 0.08 (p < 0.03) consistent with increased 11beta-HSD1 activity. There were no significant changes in truncal fat percentage (33.0 +/- 9.0 vs. 33.0 +/- 8.2) or insulin sensitivity (HOMA %S: 37.1 +/- 8.6 vs. 52.8 +/- 33.7). Modulation of cortisol metabolism during treatment of active acromegaly is dependent on changes in GH/IGF-1 status and is not influenced by any individual change in body composition or insulin sensitivity.

Buckner RL, Snyder AZ, Shannon BJ, LaRossa G, Sachs R, Fotenos AF, Sheline YI, Klunk WE, Mathis CA, Morris JC, Mintun MAMolecular, structural, and functional characterization of Alzheimer’s disease: evidence for a relationship between default activity, amyloid, and memory. J Neurosci 25:7709-7717

Article

Sep 2005
J NEUROSCI

Alzheimer's disease (AD) and antecedent factors associated with AD were explored using amyloid imaging and unbiased measures of longitudinal atrophy in combination with reanalysis of previous metabolic and functional studies. In total, data from 764 participants were compared across five in vivo imaging methods. Convergence of effects was seen in posterior cortical regions, including posterior cingulate, retrosplenial, and lateral parietal cortex. These regions were active in default states in young adults and also showed amyloid deposition in older adults with AD. At early stages of AD progression, prominent atrophy and metabolic abnormalities emerged in these posterior cortical regions; atrophy in medial temporal regions was also observed. Event-related functional magnetic resonance imaging studies further revealed that these cortical regions are active during successful memory retrieval in young adults. One possibility is that lifetime cerebral metabolism associated with regionally specific default activity predisposes cortical regions to AD-related changes, including amyloid deposition, metabolic disruption, and atrophy. These cortical regions may be part of a network with the medial temporal lobe whose disruption contributes to memory impairment.

Hippocampal and neocortical activation during repetitive encoding in older adults

Article

Feb 2006
NEUROBIOL AGING

Episodic memory function is known to decline in the course of normal aging; however, compensatory techniques can improve performance significantly in older persons. We investigated the effects of the memory enhancing technique of repetition encoding on brain activation using event-related functional magnetic resonance imaging (fMRI). Twelve healthy older adults without cognitive impairment were studied with fMRI during repetitive encoding of face-name pairs. During the first encoding trials of face-name pairs that were subsequently remembered correctly, activation of the hippocampus and multiple neocortical regions, including prefrontal, parietal and fusiform cortices, was observed. The second and third encoding trials resulted in continued activation in neocortical regions, but no task-related response within the hippocampus. Functional imaging of successful memory processes thus permits us to detect regionally specific responses in the aging brain. Our findings suggest that hippocampal function is preserved in normal aging and that repetition-based memory enhancing techniques may engage primarily neocortical attentional networks.

White Matter Lesions in an Unselected Cohort of the Elderly Molecular Pathology Suggests Origin From Chronic Hypoperfusion Injury

Article

Jun 2006
STROKE

"Incidental" MRI white matter (WM) lesions, comprising periventricular lesions (PVLs) and deep subcortical lesions (DSCLs), are common in the aging brain. Direct evidence of ischemia associated with incidental WM lesions (WMLs) has been lacking, and their pathogenesis is unresolved. A population-based, postmortem cohort (n=456) of donated brains was examined by MRI and pathology. In a subsample of the whole cohort, magnetic resonance images were used to sample and compare WMLs and nonlesional WM for molecular markers of hypoxic injury. PVL severity was associated with loss of ventricular ependyma (P=0.004). For DSCLs, there was arteriolar sclerosis compared with normal WM (vessel wall thickness and perivascular enlargement; both P<0.001). Capillary endothelial activation (ratio of intercellular adhesion molecule to basement membrane collagen IV; P<0.001) and microglial activation (CD68 expression; P=0.002) were elevated in WMLs. Immunoreactivity for hypoxia-inducible factors (HIFs) HIF1alpha and HIF2alpha was elevated in DSCLs (P=0.003 and P=0.005). Other hypoxia-regulated proteins were also increased in WMLs: matrix metalloproteinase-7 (PVLs P<0.001; DSCLs P=0.009) and the number of neuroglobin-positive cells (WMLs P=0.02) reaching statistical significance. The severity of congophilic amyloid angiopathy was associated with increased HIF1alpha expression in DSCLs (P=0.04). The data support a hypoxic environment within MRI WMLs. Persistent HIF expression may result from failure of normal adaptive mechanisms. WM ischemia appears to be a common feature of the aging brain.

Accounting for Cognitive Aging: Context Processing, Inhibition or Processing Speed?

Article

Dec 2006

Age-related deficits in context processing were examined in relationship to two predominant theories of cognitive aging (the Inhibitory Deficit and Processing Speed Models). Older and younger adults completed a measure of context processing (AX Continuous Performance Test (CPT) task) as well as a computerized battery of inhibitory tasks: Stroop, garden path sentences, go no-go, and the stop-signal paradigm. Participants also completed a simple processing speed task. After controlling for baseline differences in processing speed, age effects were detected on the AX-CPT. Smaller, but significant age effects were noted on the Stroop and stop-signal tasks, but no significant age effects were found on the garden path sentence and go no-go tasks. Intertask correlations were weak, providing little evidence for a homogenous or uniform construct of inhibition. The sensitivity of the AX-CPT to cognitive aging is discussed in the context of existing theories of cognitive aging. The authors suggest that deficits in context processing and utilization may underlie cognitive aging phenomena.

White matter lesions account for all age-related declines in speed but not in intelligence

Article

Jun 2007

MRI scans measured white matter lesion prevalence (WMLP) in 65 people ages 65-84 years who also took 17 cognitive tests: 3 tests of general fluid intelligence, 3 of vocabulary, 2 of episodic and 3 of working memory, 2 of processing speed, and 4 of frontal and executive function. Entry of age with WMLP into regression equations as predictors of test scores showed that inferences about the functional relationships between markers of brain aging and cognitive impairments are seriously misleading if they are based on simple correlations alone. A new finding that WMLP accounts for all of the age-related variance between individuals in tests of speed and executive ability but for none of the age-related variance in intelligence revises current hypotheses that gross brain changes affect general fluid intelligence and other mental abilities solely through their effects on information-processing speed.

White Matter Hyperintensities and Subclinical Infarction Associations With Psychomotor Speed and Cognitive Flexibility

Article

Apr 2008
STROKE

We examined white matter hyperintensity volume (WMHV) and subclinical infarction (no history of clinical stroke; SI) in relation to performance on tests of sequencing, cognitive flexibility, and sensorimotor ability. The Northern Manhattan Study includes a stroke-free community-based sample of Hispanic, Black, and White participants. A subsample (n=656) has undergone measurement of WMHV, SI, and neuropsychological testing. Linear regression was used to examine WMHV and SI in relation to performance on tests of sequencing as measured by Color Trails 1, cognitive flexibility as measured by Color Trails 2, and sensorimotor ability as measured by Grooved Pegboard, using generalized estimating equations (GEE) to account for the correlation among the cognitive tests and other covariates. Considering performance on the tests of sequencing, cognitive flexibility, and sensorimotor ability simultaneously using GEE, WMHV and subclinical infarction were each associated with worse cognitive performance globally. There was a threshold effect for WMHV with those in the upper quartile performing significantly worse on the tests of cognitive flexibility and sensorimotor ability. Those with frontal SI performed worse on the test of cognitive flexibility and those with deep SI, worse on the test of sequencing. Both SI and WMHV were associated with globally worse cognitive performance. Participants with WMH affecting more than 0.75% of cranial volume had significantly slower performance on a task of cognitive flexibility and sensorimotor ability than those in the lowest quartile. The effects of SI on cognitive performance varied by location.

Session II: Mechanisms of Age-Related Cognitive Change and Targets for Intervention: Neural Circuits, Networks, and Plasticity

Abstract

No full-text available

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