Advancing age results in altered cognitive and neuroimaging-derived markers of neural integrity. Whether cognitive changes are the result of variations in brain measures remains unclear and relating the two across the lifespan poses a unique set of problems. It must be determined whether statistical associations between cognitive and brain measures truly exist and are not epiphenomenal due solely to their shared relationships with age. The purpose of this study was to determine whether cerebral blood flow (CBF) and gray matter volume (GMV) measures make unique and better predictions of cognition than age alone. Multivariate analyses identified brain-wide covariance patterns from 35 healthy young and 23 healthy older adults using MRI-derived measures of CBF and GMV related to three cognitive composite scores (i.e., memory, fluid ability, and speed/attention). These brain-cognitive relationships were consistent across the age range, and not the result of epiphenomenal associations with age and each imaging modality provided its own unique information. The CBF and GMV patterns each accounted for unique aspects of cognition and accounted for nearly all the age-related variance in the cognitive composite scores. The findings suggest that measures derived from multiple imaging modalities explain larger amounts of variance in cognition providing a more complete understanding of the aging brain.
aging; multiple modality imaging; cognitive decline; cerebral blood flow; gray matter volume; multivariate analysis
Recently published guidelines suggest that the most opportune time to treat individuals with Alzheimer’s disease is during the preclinical phase of the disease. This is a phase when individuals are defined as clinically normal but exhibit evidence of amyloidosis, neurodegeneration and subtle cognitive/behavioral decline. While our standard cognitive tests are useful for detecting cognitive decline at the stage of mild cognitive impairment, they were not designed for detecting the subtle cognitive variations associated with this biomarker stage of preclinical Alzheimer’s disease. However, neuropsychologists are attempting to meet this challenge by designing newer cognitive measures and questionnaires derived from translational efforts in neuroimaging, cognitive neuroscience and clinical/experimental neuropsychology. This review is a selective summary of several novel, potentially promising, approaches that are being explored for detecting early cognitive evidence of preclinical Alzheimer’s disease in presymptomatic individuals.
Caregiving may be burdensome to caregivers, negatively affecting health and impacting decisions to institutionalize patients. It is unclear how caregiver depression changes over longer periods or whether heterogeneous trajectories for caregivers are apparent. The goals of this article are to characterize the course of depressive symptoms among caregivers over time and to examine the impact of baseline patient and caregiver characteristics on these trajectories. Patients with dementia and their caregivers were followed every 6 months for up to 6 years or until death (n = 133). Growth mixture modeling identified trajectories of caregiver depression over time. Most caregivers had stable trajectories of symptoms, with a smaller subset showing evidence of wear-and-tear. Patient clinical characteristics had no impact on symptom course for caregivers. Future work should utilize a longitudinal perspective and consider that there may be heterogeneous trajectories for caregivers. Those caregivers who follow a wear-and-tear trajectory may require targeted interventions to improve outcomes.
Randomized-controlled trials that examine the effects of Cholinesterase inhibitors (ChEI) and memantine on patient outcomes over long periods of time are difficult to conduct. Observational studies based on practice-based populations outside the context of controlled trials and open label extension studies that evaluate the effects of these medications over time are limited.
To examine in an observational study (1) relationships between ChEI and memantine use and functional and cognitive endpoints and mortality in AD patients, (2) relationships between other patient characteristics on these clinical endpoints, and (3) whether effects of the predictors change across time.
Multicenter, natural history study.
Three university-based AD centers in the US.
201 patients diagnosed with probable AD with modified Mini-Mental State Examination scores of 30 or higher at study entry followed annually for 6 years.
Discrete-time hazard analyses were used to examine relationships between ChEI and memantine use during the previous 6 months reported at each assessment and time to cognitive (Mini-Mental State Examination, MMSE≤10) and functional (Blessed Dementia Rating Scale, BDRS≥10) endpoints and mortality. Analyses controlled for clinical characteristics including baseline cognition, function, and comorbid conditions, and presence of extrapyramidal signs and psychiatric symptoms at each assessment interval. Demographic characteristics included baseline age, sex, education, and living arrangement at each assessment interval.
ChEI use was associated with delayed time in reaching functional endpoint and death. Memantine use was associated with delayed time to death. Different patient characteristics were associated with different clinical endpoints
Results suggest long term beneficial effects of ChEI and memantine on patient outcomes. As for all observational cohort study, observed relationships should not be interpreted as causal effects.
Alzheimer’s disease; cholinesterase inhibitors; memantine; outcomes; longitudinal studies
A high body mass index (BMI) in middle-age or a decrease in BMI at late-age has been considered a predictor for the development of Alzheimer's disease (AD). However, little is known about the BMI change close to or after AD onset.
BMI of participants from three cohorts, the Washington Heights and Inwood Columbia Aging Project (WHICAP; population-based) and the Predictors Study (clinic-based), and National Alzheimer's Coordinating Center (NACC; clinic-based) were analyzed longitudinally. We used generalized estimating equations to test whether there were significant changes of BMI over time, adjusting for age, sex, education, race, and research center. Stratification analyses were run to determine whether BMI changes depended on baseline BMI status.
BMI declined over time up to AD clinical onset, with an annual decrease of 0.21 (p=0.02) in WHICAP and 0.18 (p=0.04) kg/m2 in NACC. After clinical onset of AD, there was no significant decrease of BMI. BMI even increased (b=0.11, p=0.004) among prevalent AD participants in NACC. During the prodromal period, BMI decreased over time in overweight(BMI ≥25 and <30) WHICAP participants or obese (BMI≥30) NACC participants. After AD onset, BMI tended to increase in underweight/normal weight (BMI<25) patients and decrease in obese patients in all three cohorts, although the results were significant in NACC study only.
Our study suggests that while BMI declines before the clinical AD onset, it levels off after clinical AD onset, and might even increase in prevalent AD. The pattern of BMI change may also depend on the initial BMI.
Body mass index; weight; Alzheimer's disease; prospective study
Cognitive reserve (CR) is a concept meant to account for the frequent discrepancy between an individual’s measured level of brain pathology and her expected cognitive performance. It is particularly important within the context of aging and dementia, but has wider applicability to all forms of brain damage. As such, it has intimate links to related compensatory and neuroprotective concepts, as well as to the related notion of brain reserve. In this article, we introduce the concept of cognitive reserve and explicate its potential cognitive neural implementation. We conclude that cognitive reserve is compatible and complementary with many related concepts, but that each much draw sharper conceptual boundaries in order to truly explain preserved cognitive function in the face of aging or brain damage.
cognitive reserve; aging; Alzheimer’s disease; imaging; epidemiology
The hypercorrection effect, which refers to the finding that errors committed with high confidence are more likely to be corrected than are low confidence errors, has been replicated many times, and with both young adults and children. In the present study, we contrasted older with younger adults. Participants answered general-information questions, made confidence ratings about their answers, were given corrective feedback, and then were retested on questions that they had gotten wrong. While younger adults showed the hypercorrection effect, older adults, despite higher overall accuracy on the general-information questions and excellent basic metacognitive ability, showed a diminished hypercorrection effect. Indeed, the correspondence between their confidence in their errors and the probability of correction was not significantly greater than zero, showing, for the first time, that a particular participant population is selectively impaired on this error-correction task. These results potentially offer leverage both on the mechanisms underlying the hypercorrection effect and on reasons for older adults' memory impairments, as well as on memory functions that are spared.
Hypercorrection; Memory; Confidence; Older Adults; Error Correction
The theory of cognitive reserve attempts to explain why some individuals are more resilient to age-related brain pathology. Efforts to explore reserve have been hindered by measurement difficulties. Reed et al. (2010) proposed quantifying reserve as residual variance in episodic memory performance that remains after accounting for demographic factors and brain pathology (whole brain, hippocampal, and white matter hyperintensity volumes). This residual variance represents the discrepancy between an individual’s predicted and actual memory performance. The goals of the present study were to extend these methods to a larger, community-based sample and to investigate whether the residual reserve variable is explained by age, predicts longitudinal changes in language, and predicts dementia conversion independent of age. Results support this operational measure of reserve. The residual reserve variable was associated with higher reading ability, lower likelihood of meeting criteria for mild cognitive impairment, lower odds of dementia conversion independent of age, and less decline in language abilities over 3 years. Finally, the residual reserve variable moderated the negative impact of memory variance explained by brain pathology on language decline. This method has the potential to facilitate research on the mechanisms of cognitive reserve and the efficacy of interventions designed to impart reserve.
Cognition; Aging; Mild cognitive impairment; Dementia; Statistical models; Magnetic resonance imaging
This review summarizes the findings and importance of 12 articles from research at Columbia University in New York City that were among the most cited in the literature between 2006 and 2011. The 12 articles summarized in this review made important contributions to the field of Alzheimer’s disease in the last 5 years. Four of the articles established the Mediterranean diet as a food consumption pattern that may prevent Alzheimer’s disease in addition to physical activity. Two of the articles advanced our knowledge of predictors of conversion from mild cognitive impairment to dementia. Four of the articles provided important knowledge of risk factors for the progression of Alzheimer’s disease and its complications. Lastly, one of the articles laid the theoretical framework for the study of cognitive reserve, an important modifier of the manifestation of Alzheimer’s disease. These studies have advanced our knowledge about risk factors, modifiers, and progression of late onset Alzheimer’s disease.
Alzheimer’s disease; conversion; diet; cognitive reserve; epidemiology; genes; mild cognitive impairment; predictors; progression; risk factors
The concept of reserve is used to explain the observation that some individuals function better than others in the presence of brain pathology. This paper reviews the concept of reserve from its theoretical basis to the implication of reserve for clinical practice. A distinction between brain reserve, referring to individual differences in the anatomic substrate, and cognitive reserve, referring to differences in the flexibility or adaptivity of cognitive networks, is useful. Epidemiologic evidence indicates that a set of life exposures including higher educational and occupational attainment, and engaging in leisure activities is associated with a lower risk of incident dementia, suggesting that these life exposures may enhance cognitive reserve. This provides a basis for controlled clinical studies can test specific exposures that may enhance reserve. The concept of cognitive reserve also has important implications for clinical practice in terms of diagnosis and prognosis.
Numerous studies support an association between depression and increased risk of dementia. Because few studies have directly examined the temporal ordering of depression and memory decline in late life, it is not clear whether depressive symptoms typically precede and/or follow memory declines.
An autoregressive latent trajectory model examined the direction of the relationship between depressive symptoms and memory decline observed over 12 years.
Washington/Hamilton Heights Inwood Columbia Aging Project, a community-based longitudinal study of aging and dementia in Northern Manhattan.
2,425 initially non-demented older adults.
Memory composite scores were computed from three subscores of the Selective Reminding Test. Depressive symptoms were assessed with a 10-item version of the Center for Epidemiological Studies Depression Scale. Analyses controlled for age, sex, recruitment wave, education, Black race and Hispanic ethnicity measured at baseline, and chronic disease burden measured at each study visit.
Initial depressive symptoms predicted worse memory scores at the second study visit (B weight=−0.03; P=.003) as well as accelerated memory decline over the entire study period (B weight=−0.02; P=.03). Memory scores did not predict subsequent depressive symptoms.
These findings suggest that depressive symptoms precede memory decline, but not vice versa, in late life. This pattern of results is in line with hypotheses that depression is a prodrome of dementia and/or a causal contributor to memory decline. Clinicians should be aware that depressive symptoms may represent an early indicator not only of dementia, as reported previously, but also of memory decline more generally.
Depression; episodic memory; statistical modeling
The global prevalence of dementia has been estimated to be as high as 24 million, and is predicted to double every 20 years until at least 2040. As the population worldwide continues to age, the number of individuals at risk will also increase, particularly among the very old. Alzheimer disease is the leading cause of dementia beginning with impaired memory. The neuropathological hallmarks of Alzheimer disease include diffuse and neuritic extracellular amyloid plaques in brain that are frequently surrounded by dystrophic neurites and intraneuronal neurofibrillary tangles. The etiology of Alzheimer disease remains unclear, but it is likely to be the result of both genetic and environmental factors. In this review we discuss the prevalence and incidence rates, the established environmental risk factors, and the protective factors, and briefly review genetic variants predisposing to disease.
Alzheimer disease is the most frequent cause of dementia in Western societies. Advancing age and genetic and nongenetic antecedent factors (e.g., education and obesity) are thought to play important roles.
Metabolic syndrome (MetS) is defined as a clustering of metabolic disorders: abdominal obesity, dyslipidemia, hypertension, and hyperglycemia. Although specific components of MetS have been associated with white matter hyperintensities (WMH), less is known about the association between MetS as a whole and WMH, especially in normal aging. We aimed to: (1) investigate this association in a cohort of healthy elderly individuals, and (2) examine the relationship between MetS and the regional distribution of WMH, to further understanding of the relationship between MetS and structural brain changes.
Analyses were carried out on 308 participants (48.1% men, age: 71.0 ± 3.9 years) from the French longitudinal ESPRIT (Enquête de Santé Psychologique - Risques, Incidence et Traitement) study, who were free of cerebrovascular disease cognitive and functional impairment. Logistic regression models were used to examine the cross-sectional association between MetS (defined using the National Cholesterol Education Program–Adult Treatment Panel III criteria) and (1) WMH volumes, and (2) WMH volumes according to their localization in insulofrontal and temporoparietal regions.
After adjusting for potential confounders, participants with MetS had a twofold increased chance of presenting with high levels of WMH volume compared with those without (odds ratio [OR] = 2.74, 95% confidence interval [CI]: 1.25–6.03). MetS was specifically associated with an increase of temporoparietal WMH volumes, but no association was found between MetS and WMH localized in the insulofrontal region.
Our findings suggest that effective management of MetS may reduce WMH accumulation in brain areas already vulnerable to the aging process.
Epidemiology; Observational study; Elderly; Metabolic syndrome; White matter hyperintensities; Alzheimer’s disease
The global prevalence of dementia has been estimated to be as high as 24 million, and is predicted to double every 20 years until at least 2040. As the population worldwide continues to age, the number of individuals at risk will also increase, particularly among the very old. Alzheimer disease is the leading cause of dementia beginning with impaired memory. The neuropathological hallmarks of Alzheimer disease include diffuse and neuritic extracellular amyloid plaques in brain that are frequently surrounded by dystrophic neurites and intra-neuronal neurofibrillary tangles. The etiology of Alzheimer disease remains unclear, but it is likely to be the result of both genetic and environmental factors. In this review we discuss the prevalence and incidence rates, the established environmental risk factors, and the protective factors, and briefly review genetic variants predisposing to disease.
Background and Purpose
Statins are neuroprotective in a variety of experimental models of cerebral injury. We sought to determine whether patients taking statins prior to asymptomatic carotid endarterectomy (CEA) exhibit a lower incidence of neurologic injury (clinical stroke and cognitive dysfunction).
Three hundred twenty-eight (328) patients with asymptomatic carotid stenosis scheduled for elective CEA consented to participate in this observational study of perioperative neurologic injury.
Patients taking statins had a lower incidence of clinical stroke (0.0% vs. 3.1%, P=0.02) and cognitive dysfunction (11.0% vs. 20.2%, P=0.03). In a multivariate regression model, statin use was significantly associated with decreased odds of cognitive dysfunction (OR: 0.51 [0.27-0.96], P=0.04).
Pre-operative statin use was associated with less neurologic injury following asymptomatic CEA. These observations suggest that it may be possible to further reduce the perioperative morbidity of CEA.
Clinical Trial Registration-URL: http://www.ClinicalTrials.gov. Unique Identifier: NCT00597883.
The cerebral cortex of the human brain is highly folded. It is useful for neuroscientists and clinical researchers to identify and/or quantify cortical folding patterns across individuals. The top (gyri) and bottom (sulci) of these folds resemble the “blob-like” features used in computer vision. In this article, we evaluate different blob detectors and descriptors on brain MR images, and introduce our own, the “brain blob detector and descriptor (BBDD).” For the first time blob detectors are considered as spatial filters under the scale-space framework and their impulse responses are manipulated for detecting the structures in our interest. The BBDD detector is tailored to the scale and structure of blob-like features that coincide with cortical folds, and its descriptors performed well at discriminating these features in our evaluation.
Despite the intuition that strongly held beliefs are particularly difficult to change, the data on error correction indicate that general information errors that people commit with a high degree of belief are especially easy to correct. This finding is called the hypercorrection effect. The hypothesis was tested that the reason for hypercorrection stems from enhanced attention and encoding that results from a metacognitive mismatch between the person’s confidence in their responses and the true answer. This experiment, which is the first to use imaging to investigate the hyper-correction effect, provided support for this hypothesis, showing that both metacognitive mismatch conditions—that in which high confidence accompanies a wrong answer and that in which low confidence accompanies a correct answer—revealed anterior cingulate and medial frontal gyrus activations. Only in the high confidence error condition, however, was an error that conflicted with the true answer mentally present. And only the high confidence error condition yielded activations in the right TPJ and the right dorsolateral pFC. These activations suggested that, during the correction process after error commission, people (1) were entertaining both the false belief as well as the true belief (as in theory of mind tasks, which also manifest the right TPJ activation) and (2) may have been suppressing the unwanted, incorrect information that they had, themselves, produced (as in think/no-think tasks, which also manifest dorsolateral pFC activation). These error-specific processes as well as enhanced attention because of metacognitive mismatch appear to be implicated.
To examine the effect of education (a surrogate measure of cognitive reserve) on FDG-PET brain metabolism in elderly cognitively healthy (HC) subjects with preclinical Alzheimer disease (AD).
Fifty-two HC subjects (mean age 75 years) with FDG-PET and CSF measurement of Aβ1-42 were included from the prospective Alzheimer's Disease Neuroimaging Initiative biomarker study. HC subjects received a research classification of preclinical AD if CSF Aβ1-42 was <192 pg/mL (Aβ1-42 [+]) vs HC with normal Aβ (Aβ1-42 [−]). In regression analyses, we tested the interaction effect between education and CSF Aβ1-42 status (Aβ1-42 [+] vs Aβ1-42 [−]) on FDG-PET metabolism in regions of interest (ROIs) (posterior cingulate, angular gyrus, inferior/middle temporal gyrus) and the whole brain (voxel-based).
An interaction between education and CSF Aβ1-42 status was observed for FDG-PET in the posterior cingulate (p < 0.001) and angular gyrus ROIs (p = 0.03), but was not significant for the inferior/middle temporal gyrus ROI (p = 0.06), controlled for age, sex, and global cognitive ability (Alzheimer’s Disease Assessment Scale–cognitive subscale). The interaction effect was such that higher education was associated with lower FDG-PET in the Aβ1-42 (+) group, but with higher FDG-PET in the Aβ1-42 (−) group. Voxel-based analysis showed that this interaction effect was primarily restricted to temporo-parietal and ventral prefrontal brain areas.
Higher education was associated with lower FDG-PET in preclinical AD (Aβ1-42 [+]), suggesting that cognitive reserve had a compensatory function to sustain cognitive ability in presence of early AD pathology that alters FDG-PET metabolism.
Resting-state functional connectivity between neuroanatomical regions has attracted significant attention in recent years. In the process of obtaining the resting-state functional connectivity map of the human brain from blood-oxygen-level-dependent fMRI signals, it is common to average the signals from left and right hemispheres. This averaging can introduce unappreciated complexities and unintended consequences not related to the research question of interest. In this paper, we mathematically demonstrate that measures of functional connectivity obtained by averaging homologous regions from the both hemispheres become undesirably dependent on four inter-hemispheric connectivity measures. We explore this finding in real-world fMRI data from 25 healthy young participants. We show that inter-hemispheric averaging has a mixed effect on the results and may introduce correlation artifacts to the connectivity map. Furthermore, we show mathematically and demonstrate with Monte Carlo simulations of null data that inter-hemispheric averaging will not alter human brain connectivity map at rest only and if only there are no inter-hemispheric correlations.
fMRI; Resting BOLD; Brain; Functional Connectivity
Evidence suggests that individual variability in lifetime exposures influences how cognitive performance changes with advancing age. Brain maintenance and cognitive reserve are theories meant to account for preserved performance despite advancing age. These theories differ in their causal mechanisms. Brain maintenance predicts more advantageous lifetime exposures will reduce age-related neural differences. Cognitive reserve predicts that lifetime exposures will not directly reduce these differences but minimize their impact on cognitive performance. The present work used moderated-mediation modeling to investigate the contributions of these mechanisms at explaining variability in cognitive performance among a group of 39 healthy younger (mean age (standard deviation) 25.9 (2.92) and 45 healthy older adults (65.2 (2.79)). Cognitive scores were computed using composite measures from three separate domains (speed of processing, fluid reasoning, and memory), while their lifetime exposures were estimated using education and verbal IQ measures. T1-weighted MR images were used to measure cortical thickness and subcortical volumes. Results suggest a stronger role for cognitive reserve mechanisms in explaining age-related cognitive variability: even with age-related reduced gray matter, individuals with greater lifetime exposures could perform better given their quantity of brain measures.
Clinic-based studies suggest that dementia is diagnosed at older ages in bilinguals compared to monolinguals. The current study sought to test this hypothesis in a large, prospective, community-based study of initially non-demented Hispanic immigrants living in a Spanish-speaking enclave of Northern Manhattan.
Participants included 1,067 participants in the Washington/Hamilton Heights Inwood Columbia Aging Project (WHICAP) who were tested in Spanish and followed at 18–24 month intervals for up to 23 years. Spanish-English bilingualism was estimated via both self-report and an objective measure of English reading level. Multilevel models for change estimated the independent effects of bilingualism on cognitive decline in four domains: episodic memory, language, executive function, and speed. Over the course of the study, 282 participants developed dementia. Cox regression was used to estimate the independent effect of bilingualism on dementia conversion. Covariates included country of origin, gender, education, time spent in the United States, recruitment cohort, and age at enrollment.
Independent of the covariates, bilingualism was associated with better memory and executive function at baseline. However bilingualism was not independently associated with rates of cognitive decline or dementia conversion. Results were similar whether bilingualism was measured via self-report or an objective test of reading level.
This study does not support a protective effect of bilingualism on age-related cognitive decline or the development of dementia. In this sample of Hispanic immigrants, bilingualism is related to higher initial scores on cognitive tests and higher educational attainment and may not represent a unique source of cognitive reserve.
Cognitive aging; episodic memory; executive function; language; statistical modeling
Across three experiments, we examined the effect of repetition lag on priming of unfamiliar visual objects in healthy young and older adults. Multiple levels of lag were examined, ranging from short (one to four intervening stimuli) to long (50+ intervening stimuli). In each experiment, subjects viewed a series of new and repeated line drawings of objects and decided whether they depicted structurally possible or impossible figures. Experiment 1 and 2 found similar levels of priming in young and older adults at short and medium lags. At the longer repetition lags (∼20+ intervening stimuli), older adults showed less overall priming, as measured by reaction time facilitation, than young adults. This indicates that older adults can rapidly encode unfamiliar three-dimensional objects to support priming at shorter lags; however, they cannot maintain these representations over longer intervals. In addition to repetition lag, we also explored the relationship between priming and cognitive reserve, as measured by education and verbal intelligence. In the older adults, higher levels of cognitive reserve were associated with greater reaction time priming, suggesting that cognitive reserve may mediate the relationship between aging and priming.
aging; perceptual priming; unfamiliar visual objects; implicit memory; object-decision task; cognitive reserve
Disruption of the default-mode network (DMN) in healthy elders has been reported in many studies.
In a group of 51 participants (25 young, 26 elder) we examined DMN connectivity in subjects' native space. In the native space method, subject-specific regional masks (obtained independently for each subject) are used to extract regional fMRI times series. This approach substitutes the spatial normalization and subsequent smoothing used in prevailing methods, affords more accurate spatial localization, and provides the power to examine connectivity separately in the two hemispheres instead of averaging regions across hemispheres.
The native space method yielded new findings which were not detectable by the prevailing methods. The most reliable and robust disruption in elders' DMN connectivity were found between supramarginal gyrus and superior-frontal cortex in the right hemisphere only. The mean correlation between these two regions in young participants was about 0.5, and dropped significantly to 0.04 in elders (P = 2.1 × 10−5). In addition, the magnitude of functional connectivity between these regions in the right hemisphere correlated with memory (P = 0.05) and general fluid ability (P = 0.01) in elder participants and with speed of processing in young participants (P = 0.008). These relationships were not observed in the left hemisphere.
These findings suggest that analysis of DMN connectivity in subjects' native space can improve localization and power and that it is important to examine connectivity separately in each hemisphere.
Age-related brain change; cognitive performance; fMRI analysis; interhemispheric averaging; resting-state BOLD fMRI; spatial normalization; SPM