We examined the effects of dorsal, ventral, or complete damage to the hippocampus on long‐term re... more We examined the effects of dorsal, ventral, or complete damage to the hippocampus on long‐term retention of a Pavlovian conditioned fear response to a tone and a context paired with foot shock. Rats received a fear conditioning episode, in which a tone and context or context‐alone were paired with foot shock. Two days or 12 weeks later, they received sham, dorsal, ventral, or complete NMDA‐induced damage of the hippocampus. During a retention test conducted 2 weeks after surgery, the sham control rats exhibited high levels of freezing in the context and in the presence of the tone. Rats with dorsal, ventral, or complete hippocampal damage displayed very little freezing in the context at either learning‐surgery intervals. Partial hippocampal damage tended to cause a smaller but consistent deficit in conditioned responding to context at the shorter (2 day) learning‐surgery interval. Rats with hippocampal damage did not display less severe retrograde amnesia for more remote (12 weeks) ...
Background: Emerging evidence suggests that age-related changes in cerebral health may be sensiti... more Background: Emerging evidence suggests that age-related changes in cerebral health may be sensitive to vascular risk modifiers, such as physical activity and sleep. Objective: We examine whether cardiorespiratory fitness modifies the association of obstructive sleep apnea (OSA) severity with MRI-assessed measures of cerebral structure and perfusion. Methods: Using data from a cross-sectional sample of participants (n = 129, 51% female, age range 49.6-85.3 years) in the Wisconsin Sleep Cohort study, we estimated linear models of MRI-assessed total and regional gray matter (GM) and white matter (WM) volumes, WM hyperintensity (WMH:ICV ratio), total lesion volume, and arterial spin labeling (ASL) cerebral blood flow (CBF), using an estimated measure of cardiorespiratory fitness (CRF) and OSA severity as predictors. Participants’ sleep was assessed using overnight in-laboratory polysomnography, and OSA severity was measured using the apnea-hypopnea index (AHI), or the mean number of recorded apnea and hypopnea events per hour of sleep. The mean±SD time difference between PSG data collection and MRI data collection was 1.7±1.5 years (range: [0, 4.9 years]). Results: OSA severity was associated with reduced total GM volume (β=-0.064; SE = 0.023; p = 0.007), greater total WM lesion volume (interaction p = 0.023), and greater WMHs (interaction p = 0.017) in less-fit subjects. Perfusion models revealed significant differences in the association of AHI and regional CBF between fitness groups (interaction ps < 0.05). Conclusion: This work provides new evidence for the protective role of cardiorespiratory fitness against the deleterious effects of OSA on brain aging in late-middle age to older adults.
We investigated human place learning in a computerized version of the Morris water task (VMWT) un... more We investigated human place learning in a computerized version of the Morris water task (VMWT) under comparable conditions to those employed by Sutherland et al. (Sutherland et al. Psychobiology, 1987;15:48-57) with rats. Participants viewed a computer-generated environment and were trained to locate a hidden goal in one half of a circular pool (region 1). The opportunity to navigate in and view cues from region 2 was systematically varied during training. Participants were then started from region 2 to assess transfer. Accurate transfer performance was dependent upon prior experience viewing distal cues from region 2 while on a trajectory to the goal, a finding we interpret as inconsistent with the automatic formation and modification of a cognitive map (O'Keefe J, Nadel L. The Hippocampus as a cognitive map. Oxford, UK: Clarendon Press, 1978). Additionally, the transfer data reported here closely match the data obtained by Sutherland et al. with rats suggesting some generality in the principles involved in place learning.
Background: Besides its well-established role in nerve cell survival and adaptive plasticity, bra... more Background: Besides its well-established role in nerve cell survival and adaptive plasticity, brain-derived neurotrophic factor (BDNF) is also involved in energy homeostasis and cardiovascular regulation. Although BDNF is present in the systemic circulation, it is unknown whether plasma BDNF correlates with circulating markers of dysregulated metabolism and an adverse cardiovascular profile. Methodology/Principal Findings: To determine whether circulating BDNF correlates with indices of metabolic and cardiovascular health, we measured plasma BDNF levels in 496 middle-age and elderly subjects (mean age ,70), in the Baltimore Longitudinal Study of Aging. Linear regression analysis revealed that plasma BDNF is associated with risk factors for cardiovascular disease and metabolic syndrome, regardless of age. In females, BDNF was positively correlated with BMI, fat mass, diastolic blood pressure, total cholesterol, and LDL-cholesterol, and inversely correlated with folate. In males, BDNF was positively correlated with diastolic blood pressure, triglycerides, free thiiodo-thyronine (FT3), and bioavailable testosterone, and inversely correlated with sex-hormone binding globulin, and adiponectin. Conclusion/Significance: Plasma BDNF significantly correlates with multiple risk factors for metabolic syndrome and cardiovascular dysfunction. Whether BDNF contributes to the pathogenesis of these disorders or functions in adaptive responses to cellular stress (as occurs in the brain) remains to be determined.
Aging is often accompanied by learning and memory problems, many of which resemble deficits assoc... more Aging is often accompanied by learning and memory problems, many of which resemble deficits associated with hippocampal damage. Studies of aging in nonhuman animals have demonstrated hippocampus-related memory decline, and point to a possible locus for impairments associated with normal and pathological aging in humans. Two well-characterized hippocampus-dependent tasks in nonhuman animal literature are the Morris water task (MWT) and the transverse patterning discrimination task (TPDT). We employed the virtual MWT and the TPDT to assess hippocampus-dependent cognition in humans. Magnetic resonance imaging and proton magnetic resonance spectroscopy were employed to measure hippocampal volume and neurochemistry respectively. Age-related deficits were observed in performance on both hippocampus-dependent tasks. This pattern of impairment was accompanied by decreased hippocampal NAA/Cre ratios and volume, both of which imply neuronal loss and/or decrease in neuronal density. Collectively, our results suggest that hippocampus undergoes structural and biochemical changes with normal aging and that these changes may represent an important component of age-related deterioration in hippocampusdependent cognition.
Carolina Digital Repository (University of North Carolina at Chapel Hill), 2015
Objective-To examine the putative adverse effects of ambient fine particulate matter (PM 2.5) on ... more Objective-To examine the putative adverse effects of ambient fine particulate matter (PM 2.5) on brain volumes in older women.
Before 2002, hormone therapy (HT) was commonly prescribed to restore naturally diminishing hormon... more Before 2002, hormone therapy (HT) was commonly prescribed to restore naturally diminishing hormonal levels during and after menopause. HT was also thought to prevent many health conditions faced by menopausal women, including osteoporosis, heart disease, cancer, and dementia. Support for these claims came primarily from epidemiological studies and basic research suggesting biological plausibility. Women now live a third of their life beyond ovarian function cessation. Given that cognitive impairment and dementia increase with age, increasing life expectancy may result in greater public health consequences. This chapter reviews the potential risks and benefits of HT, with a focus on cognitive function. It also discusses the implications of menopausal HT on cognitive impairment and dementia prevention, diagnosis, and treatment for aging women.
BackgroundEmerging evidence suggests that age‐related changes in cerebral structure and perfusion... more BackgroundEmerging evidence suggests that age‐related changes in cerebral structure and perfusion—hallmark features of preclinical Alzheimer’s disease (AD)—may be sensitive to vascular risk modifiers such as physical exercise and sleep quality. Here, we examine whether cardiorespiratory fitness modifies the effects of obstructive sleep apnea (OSA) on cerebral structure, perfusion, and AD risk.MethodUsing data from a sample of participants (n=134 for analyses of imaging outcomes and n=1,182 for analyses examining AD outcomes) in the Wisconsin Sleep Cohort (WSC) study, we examined cross‐sectional associations between OSA severity, estimated cardiorespiratory fitness (eCRF), and their interaction with MRI‐assessed total and regional gray (GM) and white matter (WM) volumes, WM hyperintensities (WMHs), total lesion volume, and arterial spin labeling cerebral blood flow (CBF), using multiple linear regression models adjusted for age, sex, BMI, hypertension, and education level. We further assessed whether eCRF modifies the associations between OSA and risk of AD using Cox proportional hazard models.ResultOSA severity was associated with greater total lesion volume, reduced total GM volume, and greater WMHs among less‐fit, but not among more‐fit, subjects. Perfusion models likewise revealed significant regional differences in CBF between fitness groups. OSA severity was likewise associated with greater risk of AD among less‐fit individuals, but there was no significant association among the more‐fit.ConclusionThis work provides new evidence for the protective role of cardiorespiratory fitness against the deleterious effects of OSA on brain aging and AD.
Certain cognitive processes, including spatial ability, decline with normal aging. Spatial abilit... more Certain cognitive processes, including spatial ability, decline with normal aging. Spatial ability is also a cognitive domain with robust sex differences typically favoring males. However, tests of spatial ability do not seem to measure a homogeneous class of processes. For many, mentally matching rotated three-dimensional images is the gold standard for measuring spatial cognition in humans, while the Morris water task (MWT) is a preferred method in the domain of nonhuman animal research. The MWT is sensitive to hippocampal damage, a structure critical for normal learning and memory and often implicated in age-related cognitive decline. A computerized (virtual) version of the MWT (VMWT) appears to require and engage human hippocampal circuitry, and has proven useful in studying sex differences and testing spatial learning theories. In Experiment 1, we tested participants (20-90 years of age) in the VMWT and compared their performance to that on the Vandenberg Mental Rotation Test. We report an age-related deficit in performance on both tasks. In Experiment 2, we tested young (age 20-39) and elderly (age N60) participants in the VMWT and correlated their performance to the circulating levels of testosterone and cortisol. Our findings indicate that the persistence of male spatial advantage may be related to circulating testosterone, but not cortisol levels, and independent of generalized age-related cognitive decline.
Journal of Alzheimers Disease & Parkinsonism, Nov 22, 2013
A lzheimer's disease (AD), an age-related neurodegenerative disorder and the most common cause of... more A lzheimer's disease (AD), an age-related neurodegenerative disorder and the most common cause of dementia, represents the culmination of neuropathological changes thought to evolve over several decades. Recent findings from prospective longitudinal studies with autopsy component suggest that neuritic plaques and neurofibrillary tangles, the neuropathological hallmarks of AD, are not limited to individuals with dementia. These 'hallmark' pathologic changes can also be present in the brains of clinically normal older adults-a condition we defined as Asymptomatic AD (ASYMAD). I will review the historical background and highlight the combined clinical, pathologic and morphometric evidence related to ASYMAD from the Baltimore Longitudinal Study of Aging (BLSA). The BLSA was established in 1958, supported since by the National Institute on Aging (NIA) intramural research program, with an autopsy program in place since 1986 in combination with comprehensive neurologic and cognitive evaluations. Although it remains unclear whether ASYMAD individuals would remain clinically normal with longer survival, our findings suggest that they seem to be able to compensate for or delay the appearance of clinical symptoms well into old age. Understanding the nature of changes during this apparently asymptomatic state may shed light on the mechanisms that forestall the progression of the disease and allow for maintenance of cognitive health, an important area of research that has been understudied relative to the identification of risks and pathways to negative health outcomes.
We evaluated the role of the neurotoxicant lead (Pb) in mediating racial disparities in later-lif... more We evaluated the role of the neurotoxicant lead (Pb) in mediating racial disparities in later-life cognition in 1,085 non-Hispanic Black and 2,839 non-Hispanic white participants in NHANES (1999-2002, 2011-2014) 60+ years of age. We operationalized Black race as a marker for the experience of racialization and exposure to systemic racism. We estimated patella bone Pb via predictive models using blood Pb and demographics. Concurrent cognition (processing speed, sustained attention, working memory) was measured by the Digit Symbol Substitution Test (DSST) and a global measure combining four cognitive tests. To obtain the portion mediated, we used regression coefficients (race on Pb * Pb on cognitive score)/(race on cognitive score), adjusting for age, NHANES cycle, and sample weights. Other confounder adjustment (education, poverty income ratio, smoking) was limited to the mediator-outcome (i.e., Pb-cognition) pathway because these factors do not lie upstream of race and so cannot con...
The human brain, composed of billions of neurons and synaptic connections, is an intricate networ... more The human brain, composed of billions of neurons and synaptic connections, is an intricate network coordinating a sophisticated balance of excitatory and inhibitory activity between brain regions. The dynamical balance between excitation and inhibition is vital for adjusting neural input/output relationships in cortical networks and regulating the dynamic range of their responses to stimuli. To infer this balance using connectomics, we recently introduced a computational framework based on the Ising model, first developed to explain phase transitions in ferromagnets, and proposed a novel hybrid resting-state structural connectome (rsSC). Here, we show that a generative model based on the Kuramoto phase oscillator can be used to simulate static and dynamic functional connectomes (FC) with rsSC as the coupling weight coefficients, such that the simulated FC well aligns with the observed FC when compared to that simulated with traditional structural connectome. Simulations were perform...
Objective Reversal learning (RL) tasks, known to be frontal-lobe dependent, are frequently used i... more Objective Reversal learning (RL) tasks, known to be frontal-lobe dependent, are frequently used in experimental paradigms to assess components of executive function. Extant literature has historically focused on measures of accuracy as their primary outcome, but reaction time (RT) has not yet been well examined. The present study thoroughly examines RT in order to better characterize RL performance and how it changes with age. Method 182 healthy aging participants completed a RL task, including 43 young (ages 18-30) and 139 community dwelling middle-aged adults (ages 40-61). In order to identify the best predictors of age among RL performance, an adaptive elastic net generalized regression with Poisson distribution modeling and Akakie information criteria (AIC) penalty was utilized. Variables were included from the Diffusion model (a, v, t0), ex-Gaussian distribution (mu, sigma, tau), Normal-3 Mixture distribution (location1-3, dispersion1-3, probability1-3), and RL trials-to-criter...
Removal of the medial prefrontal cortex (mPFC) of the rat during the initial 7-12 days of life re... more Removal of the medial prefrontal cortex (mPFC) of the rat during the initial 7-12 days of life results in spontaneous filling of lesion cavity that is accompanied by recovery of cognitive and motor functions. To date, it remains uncertain whether tissue filling the lesion cavity is actually supporting the functional improvement. In the present study, we examined whether spontaneous neuronal activity could be recorded in adulthood from the tissue that fills the lesion cavity. We recorded EEG and multiunit activity in adulthood from the mPFC and the motor cortex of rats that had received neonatal mPFC lesions on post-natal day 10 (P10) or their non-lesioned littermate controls. We found similarities in both the firing pattern and firing rate of cells from the filled-in region compared to that of controls, although the power associated with peak frequencies in the delta, alpha, and beta range in the EEG recorded from the filled-in region was lower compared to controls. Overall, our results suggest that the cells found in the lesion cavity have similar neurophysiological properties to those found in normal tissue and thus should be capable of at least partially supporting the observed recovery of function.
BackgroundAmbient air pollution exposures increase the risk of Alzheimer’s disease (AD) and relat... more BackgroundAmbient air pollution exposures increase the risk of Alzheimer’s disease (AD) and related dementias, which may be driven by structural brain alterations in the medial temporal lobe (MTL). The MTL consists of subregions critical for memory and vulnerable to AD neuropathology, including the hippocampus, parahippocampal gyrus (PHG), entorhinal cortex (ERC), and amygdala. However, previous structural MRI studies examining the hypothesized adverse effects of exposure on MTL were cross‐sectional and largely focused on hippocampus which yielded mixed results, failing to provide insights on the underlying neuropathological processes affected by air pollution exposures.MethodWe conducted a longitudinal study including 653 cognitively‐normal community‐dwelling women from the Women’s Health Initiative Memory Study with two MRI brain scans (MRI‐1: 2005‐6; MRI‐2: 2010‐11; Meanage at MRI‐1 = 77.3±3.5). Using regionalized universal kriging models, exposures at residential locations were ...
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
IntroductionDementia as an inevitable aging consequence has been challenged and underscores the n... more IntroductionDementia as an inevitable aging consequence has been challenged and underscores the need for investigations of the factors that confer resilience. We examine whether the functionally advantageous KL‐VS variant of the putative aging suppressor KLOTHO gene attenuates age‐related cognitive decline and deleterious biomolecular changes.MethodsTrajectories of change in memory and executive function (N = 360; 2–12 visits) and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers—amyloid beta (Aβ)42, total tau (t‐tau), phosphorylated tau (p‐tau) (N = 112; 2–4 samplings)—were compared between KL‐VS non‐carriers and heterozygotes in middle‐aged and older adults from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center studies.ResultsMemory and executive function declined (p’s 0.001) and CSF t‐tau, p‐tau, t‐tau/Aβ42, and p‐tau/Aβ42 levels increased (all p’s 0.004) with age. The rate of p‐tau accumulation was att...
We examined the effects of dorsal, ventral, or complete damage to the hippocampus on long‐term re... more We examined the effects of dorsal, ventral, or complete damage to the hippocampus on long‐term retention of a Pavlovian conditioned fear response to a tone and a context paired with foot shock. Rats received a fear conditioning episode, in which a tone and context or context‐alone were paired with foot shock. Two days or 12 weeks later, they received sham, dorsal, ventral, or complete NMDA‐induced damage of the hippocampus. During a retention test conducted 2 weeks after surgery, the sham control rats exhibited high levels of freezing in the context and in the presence of the tone. Rats with dorsal, ventral, or complete hippocampal damage displayed very little freezing in the context at either learning‐surgery intervals. Partial hippocampal damage tended to cause a smaller but consistent deficit in conditioned responding to context at the shorter (2 day) learning‐surgery interval. Rats with hippocampal damage did not display less severe retrograde amnesia for more remote (12 weeks) ...
Background: Emerging evidence suggests that age-related changes in cerebral health may be sensiti... more Background: Emerging evidence suggests that age-related changes in cerebral health may be sensitive to vascular risk modifiers, such as physical activity and sleep. Objective: We examine whether cardiorespiratory fitness modifies the association of obstructive sleep apnea (OSA) severity with MRI-assessed measures of cerebral structure and perfusion. Methods: Using data from a cross-sectional sample of participants (n = 129, 51% female, age range 49.6-85.3 years) in the Wisconsin Sleep Cohort study, we estimated linear models of MRI-assessed total and regional gray matter (GM) and white matter (WM) volumes, WM hyperintensity (WMH:ICV ratio), total lesion volume, and arterial spin labeling (ASL) cerebral blood flow (CBF), using an estimated measure of cardiorespiratory fitness (CRF) and OSA severity as predictors. Participants’ sleep was assessed using overnight in-laboratory polysomnography, and OSA severity was measured using the apnea-hypopnea index (AHI), or the mean number of recorded apnea and hypopnea events per hour of sleep. The mean±SD time difference between PSG data collection and MRI data collection was 1.7±1.5 years (range: [0, 4.9 years]). Results: OSA severity was associated with reduced total GM volume (β=-0.064; SE = 0.023; p = 0.007), greater total WM lesion volume (interaction p = 0.023), and greater WMHs (interaction p = 0.017) in less-fit subjects. Perfusion models revealed significant differences in the association of AHI and regional CBF between fitness groups (interaction ps < 0.05). Conclusion: This work provides new evidence for the protective role of cardiorespiratory fitness against the deleterious effects of OSA on brain aging in late-middle age to older adults.
We investigated human place learning in a computerized version of the Morris water task (VMWT) un... more We investigated human place learning in a computerized version of the Morris water task (VMWT) under comparable conditions to those employed by Sutherland et al. (Sutherland et al. Psychobiology, 1987;15:48-57) with rats. Participants viewed a computer-generated environment and were trained to locate a hidden goal in one half of a circular pool (region 1). The opportunity to navigate in and view cues from region 2 was systematically varied during training. Participants were then started from region 2 to assess transfer. Accurate transfer performance was dependent upon prior experience viewing distal cues from region 2 while on a trajectory to the goal, a finding we interpret as inconsistent with the automatic formation and modification of a cognitive map (O'Keefe J, Nadel L. The Hippocampus as a cognitive map. Oxford, UK: Clarendon Press, 1978). Additionally, the transfer data reported here closely match the data obtained by Sutherland et al. with rats suggesting some generality in the principles involved in place learning.
Background: Besides its well-established role in nerve cell survival and adaptive plasticity, bra... more Background: Besides its well-established role in nerve cell survival and adaptive plasticity, brain-derived neurotrophic factor (BDNF) is also involved in energy homeostasis and cardiovascular regulation. Although BDNF is present in the systemic circulation, it is unknown whether plasma BDNF correlates with circulating markers of dysregulated metabolism and an adverse cardiovascular profile. Methodology/Principal Findings: To determine whether circulating BDNF correlates with indices of metabolic and cardiovascular health, we measured plasma BDNF levels in 496 middle-age and elderly subjects (mean age ,70), in the Baltimore Longitudinal Study of Aging. Linear regression analysis revealed that plasma BDNF is associated with risk factors for cardiovascular disease and metabolic syndrome, regardless of age. In females, BDNF was positively correlated with BMI, fat mass, diastolic blood pressure, total cholesterol, and LDL-cholesterol, and inversely correlated with folate. In males, BDNF was positively correlated with diastolic blood pressure, triglycerides, free thiiodo-thyronine (FT3), and bioavailable testosterone, and inversely correlated with sex-hormone binding globulin, and adiponectin. Conclusion/Significance: Plasma BDNF significantly correlates with multiple risk factors for metabolic syndrome and cardiovascular dysfunction. Whether BDNF contributes to the pathogenesis of these disorders or functions in adaptive responses to cellular stress (as occurs in the brain) remains to be determined.
Aging is often accompanied by learning and memory problems, many of which resemble deficits assoc... more Aging is often accompanied by learning and memory problems, many of which resemble deficits associated with hippocampal damage. Studies of aging in nonhuman animals have demonstrated hippocampus-related memory decline, and point to a possible locus for impairments associated with normal and pathological aging in humans. Two well-characterized hippocampus-dependent tasks in nonhuman animal literature are the Morris water task (MWT) and the transverse patterning discrimination task (TPDT). We employed the virtual MWT and the TPDT to assess hippocampus-dependent cognition in humans. Magnetic resonance imaging and proton magnetic resonance spectroscopy were employed to measure hippocampal volume and neurochemistry respectively. Age-related deficits were observed in performance on both hippocampus-dependent tasks. This pattern of impairment was accompanied by decreased hippocampal NAA/Cre ratios and volume, both of which imply neuronal loss and/or decrease in neuronal density. Collectively, our results suggest that hippocampus undergoes structural and biochemical changes with normal aging and that these changes may represent an important component of age-related deterioration in hippocampusdependent cognition.
Carolina Digital Repository (University of North Carolina at Chapel Hill), 2015
Objective-To examine the putative adverse effects of ambient fine particulate matter (PM 2.5) on ... more Objective-To examine the putative adverse effects of ambient fine particulate matter (PM 2.5) on brain volumes in older women.
Before 2002, hormone therapy (HT) was commonly prescribed to restore naturally diminishing hormon... more Before 2002, hormone therapy (HT) was commonly prescribed to restore naturally diminishing hormonal levels during and after menopause. HT was also thought to prevent many health conditions faced by menopausal women, including osteoporosis, heart disease, cancer, and dementia. Support for these claims came primarily from epidemiological studies and basic research suggesting biological plausibility. Women now live a third of their life beyond ovarian function cessation. Given that cognitive impairment and dementia increase with age, increasing life expectancy may result in greater public health consequences. This chapter reviews the potential risks and benefits of HT, with a focus on cognitive function. It also discusses the implications of menopausal HT on cognitive impairment and dementia prevention, diagnosis, and treatment for aging women.
BackgroundEmerging evidence suggests that age‐related changes in cerebral structure and perfusion... more BackgroundEmerging evidence suggests that age‐related changes in cerebral structure and perfusion—hallmark features of preclinical Alzheimer’s disease (AD)—may be sensitive to vascular risk modifiers such as physical exercise and sleep quality. Here, we examine whether cardiorespiratory fitness modifies the effects of obstructive sleep apnea (OSA) on cerebral structure, perfusion, and AD risk.MethodUsing data from a sample of participants (n=134 for analyses of imaging outcomes and n=1,182 for analyses examining AD outcomes) in the Wisconsin Sleep Cohort (WSC) study, we examined cross‐sectional associations between OSA severity, estimated cardiorespiratory fitness (eCRF), and their interaction with MRI‐assessed total and regional gray (GM) and white matter (WM) volumes, WM hyperintensities (WMHs), total lesion volume, and arterial spin labeling cerebral blood flow (CBF), using multiple linear regression models adjusted for age, sex, BMI, hypertension, and education level. We further assessed whether eCRF modifies the associations between OSA and risk of AD using Cox proportional hazard models.ResultOSA severity was associated with greater total lesion volume, reduced total GM volume, and greater WMHs among less‐fit, but not among more‐fit, subjects. Perfusion models likewise revealed significant regional differences in CBF between fitness groups. OSA severity was likewise associated with greater risk of AD among less‐fit individuals, but there was no significant association among the more‐fit.ConclusionThis work provides new evidence for the protective role of cardiorespiratory fitness against the deleterious effects of OSA on brain aging and AD.
Certain cognitive processes, including spatial ability, decline with normal aging. Spatial abilit... more Certain cognitive processes, including spatial ability, decline with normal aging. Spatial ability is also a cognitive domain with robust sex differences typically favoring males. However, tests of spatial ability do not seem to measure a homogeneous class of processes. For many, mentally matching rotated three-dimensional images is the gold standard for measuring spatial cognition in humans, while the Morris water task (MWT) is a preferred method in the domain of nonhuman animal research. The MWT is sensitive to hippocampal damage, a structure critical for normal learning and memory and often implicated in age-related cognitive decline. A computerized (virtual) version of the MWT (VMWT) appears to require and engage human hippocampal circuitry, and has proven useful in studying sex differences and testing spatial learning theories. In Experiment 1, we tested participants (20-90 years of age) in the VMWT and compared their performance to that on the Vandenberg Mental Rotation Test. We report an age-related deficit in performance on both tasks. In Experiment 2, we tested young (age 20-39) and elderly (age N60) participants in the VMWT and correlated their performance to the circulating levels of testosterone and cortisol. Our findings indicate that the persistence of male spatial advantage may be related to circulating testosterone, but not cortisol levels, and independent of generalized age-related cognitive decline.
Journal of Alzheimers Disease & Parkinsonism, Nov 22, 2013
A lzheimer's disease (AD), an age-related neurodegenerative disorder and the most common cause of... more A lzheimer's disease (AD), an age-related neurodegenerative disorder and the most common cause of dementia, represents the culmination of neuropathological changes thought to evolve over several decades. Recent findings from prospective longitudinal studies with autopsy component suggest that neuritic plaques and neurofibrillary tangles, the neuropathological hallmarks of AD, are not limited to individuals with dementia. These 'hallmark' pathologic changes can also be present in the brains of clinically normal older adults-a condition we defined as Asymptomatic AD (ASYMAD). I will review the historical background and highlight the combined clinical, pathologic and morphometric evidence related to ASYMAD from the Baltimore Longitudinal Study of Aging (BLSA). The BLSA was established in 1958, supported since by the National Institute on Aging (NIA) intramural research program, with an autopsy program in place since 1986 in combination with comprehensive neurologic and cognitive evaluations. Although it remains unclear whether ASYMAD individuals would remain clinically normal with longer survival, our findings suggest that they seem to be able to compensate for or delay the appearance of clinical symptoms well into old age. Understanding the nature of changes during this apparently asymptomatic state may shed light on the mechanisms that forestall the progression of the disease and allow for maintenance of cognitive health, an important area of research that has been understudied relative to the identification of risks and pathways to negative health outcomes.
We evaluated the role of the neurotoxicant lead (Pb) in mediating racial disparities in later-lif... more We evaluated the role of the neurotoxicant lead (Pb) in mediating racial disparities in later-life cognition in 1,085 non-Hispanic Black and 2,839 non-Hispanic white participants in NHANES (1999-2002, 2011-2014) 60+ years of age. We operationalized Black race as a marker for the experience of racialization and exposure to systemic racism. We estimated patella bone Pb via predictive models using blood Pb and demographics. Concurrent cognition (processing speed, sustained attention, working memory) was measured by the Digit Symbol Substitution Test (DSST) and a global measure combining four cognitive tests. To obtain the portion mediated, we used regression coefficients (race on Pb * Pb on cognitive score)/(race on cognitive score), adjusting for age, NHANES cycle, and sample weights. Other confounder adjustment (education, poverty income ratio, smoking) was limited to the mediator-outcome (i.e., Pb-cognition) pathway because these factors do not lie upstream of race and so cannot con...
The human brain, composed of billions of neurons and synaptic connections, is an intricate networ... more The human brain, composed of billions of neurons and synaptic connections, is an intricate network coordinating a sophisticated balance of excitatory and inhibitory activity between brain regions. The dynamical balance between excitation and inhibition is vital for adjusting neural input/output relationships in cortical networks and regulating the dynamic range of their responses to stimuli. To infer this balance using connectomics, we recently introduced a computational framework based on the Ising model, first developed to explain phase transitions in ferromagnets, and proposed a novel hybrid resting-state structural connectome (rsSC). Here, we show that a generative model based on the Kuramoto phase oscillator can be used to simulate static and dynamic functional connectomes (FC) with rsSC as the coupling weight coefficients, such that the simulated FC well aligns with the observed FC when compared to that simulated with traditional structural connectome. Simulations were perform...
Objective Reversal learning (RL) tasks, known to be frontal-lobe dependent, are frequently used i... more Objective Reversal learning (RL) tasks, known to be frontal-lobe dependent, are frequently used in experimental paradigms to assess components of executive function. Extant literature has historically focused on measures of accuracy as their primary outcome, but reaction time (RT) has not yet been well examined. The present study thoroughly examines RT in order to better characterize RL performance and how it changes with age. Method 182 healthy aging participants completed a RL task, including 43 young (ages 18-30) and 139 community dwelling middle-aged adults (ages 40-61). In order to identify the best predictors of age among RL performance, an adaptive elastic net generalized regression with Poisson distribution modeling and Akakie information criteria (AIC) penalty was utilized. Variables were included from the Diffusion model (a, v, t0), ex-Gaussian distribution (mu, sigma, tau), Normal-3 Mixture distribution (location1-3, dispersion1-3, probability1-3), and RL trials-to-criter...
Removal of the medial prefrontal cortex (mPFC) of the rat during the initial 7-12 days of life re... more Removal of the medial prefrontal cortex (mPFC) of the rat during the initial 7-12 days of life results in spontaneous filling of lesion cavity that is accompanied by recovery of cognitive and motor functions. To date, it remains uncertain whether tissue filling the lesion cavity is actually supporting the functional improvement. In the present study, we examined whether spontaneous neuronal activity could be recorded in adulthood from the tissue that fills the lesion cavity. We recorded EEG and multiunit activity in adulthood from the mPFC and the motor cortex of rats that had received neonatal mPFC lesions on post-natal day 10 (P10) or their non-lesioned littermate controls. We found similarities in both the firing pattern and firing rate of cells from the filled-in region compared to that of controls, although the power associated with peak frequencies in the delta, alpha, and beta range in the EEG recorded from the filled-in region was lower compared to controls. Overall, our results suggest that the cells found in the lesion cavity have similar neurophysiological properties to those found in normal tissue and thus should be capable of at least partially supporting the observed recovery of function.
BackgroundAmbient air pollution exposures increase the risk of Alzheimer’s disease (AD) and relat... more BackgroundAmbient air pollution exposures increase the risk of Alzheimer’s disease (AD) and related dementias, which may be driven by structural brain alterations in the medial temporal lobe (MTL). The MTL consists of subregions critical for memory and vulnerable to AD neuropathology, including the hippocampus, parahippocampal gyrus (PHG), entorhinal cortex (ERC), and amygdala. However, previous structural MRI studies examining the hypothesized adverse effects of exposure on MTL were cross‐sectional and largely focused on hippocampus which yielded mixed results, failing to provide insights on the underlying neuropathological processes affected by air pollution exposures.MethodWe conducted a longitudinal study including 653 cognitively‐normal community‐dwelling women from the Women’s Health Initiative Memory Study with two MRI brain scans (MRI‐1: 2005‐6; MRI‐2: 2010‐11; Meanage at MRI‐1 = 77.3±3.5). Using regionalized universal kriging models, exposures at residential locations were ...
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
IntroductionDementia as an inevitable aging consequence has been challenged and underscores the n... more IntroductionDementia as an inevitable aging consequence has been challenged and underscores the need for investigations of the factors that confer resilience. We examine whether the functionally advantageous KL‐VS variant of the putative aging suppressor KLOTHO gene attenuates age‐related cognitive decline and deleterious biomolecular changes.MethodsTrajectories of change in memory and executive function (N = 360; 2–12 visits) and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers—amyloid beta (Aβ)42, total tau (t‐tau), phosphorylated tau (p‐tau) (N = 112; 2–4 samplings)—were compared between KL‐VS non‐carriers and heterozygotes in middle‐aged and older adults from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center studies.ResultsMemory and executive function declined (p’s 0.001) and CSF t‐tau, p‐tau, t‐tau/Aβ42, and p‐tau/Aβ42 levels increased (all p’s 0.004) with age. The rate of p‐tau accumulation was att...
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Papers by Ira Driscoll