September 1-8, 2017
Coordinator: John H. Morrison
University of California, Davis. USA
Roberta Brinton, University of Southern California, Los Angeles, USA
Mark Baxter, Icahn School of Medicine at Mount Sinai, New York, USA
Tara Spires-Jones, University of Edinburgh, UK
Jennifer Bizon, University of Florida, Gainesville, USA
Naftali Raz, Wayne State University, Detroit, USA
Ulman Lindenberger, Max Planck Institute for Human Development, Berlin, Germany
John H. Morrison, University of California, Davis, USA
From Act IV, scene 7 in King Lear, by William Shakespeare (1605):
“I fear I am not in my perfect mind.
Methinks I should know you and know this man;
Yet, I am doubtful; for I am mainly ignorant
What place this is; and all the skill I have
Remembers not these garments; nor I know not
Where I did lodge last night. Do not laugh at me.”
From “It’s Alright, Ma (I’m Only Bleeding) by Bob Dylan (1964):
“He not busy being born is busy dying.”
Does King Lear have early Alzheimer’s Disease (AD) or is he reflecting the confusion and cognitive problems often seen in the elderly but short of dementia? Is Bob Dylan talking about a neuron or a person? Or is he telling us that remaining active and feeding your synapses is the best way to remain “Forever Young”? The interface between cognitive aging that might be considered normal, or at least not devastating, and the early stages of AD has fascinated neuroscientists, neurologists, and perhaps writers for a long time. That interface and whether one is likely to progress from cognitive decline to AD also fills elderly people with fear. This Advanced Course will focus primarily on the events that lead to cognitive decline in the absence of AD, but we will also discuss mechanisms that might be relevant to both conditions. While it is quite clear that the dementia of AD results from neuron death, particularly in circuits that mediate learning and memory, it is equally clear that age-related cognitive decline does not result from neuron death and is thus not a mild form of AD. Age-related cognitive decline appears to result primarily from synaptic alterations and other changes that affect neuronal communication in circuits mediating learning and memory that are still intact. These circuits must retain synaptic health in order to function properly, and certain events associated with aging lead to declining synaptic health. What is the nature of these age-related alterations and what causes them? Can they be prevented or treated? What are the mechanisms involved in synaptic aging and are they in any way similar to those implicated in neuron death? How do these synaptic alterations lead to cognitive decline? Why is cognition so vulnerable to aging? Do brain regions age differently and at different rates? Are there changes across the lifespan or does cognitive aging and its neurobiological causes occur suddenly?
We will address these issues and more in this Advanced Course. The week will start with a comprehensive treatment of the regions and circuits that mediate learning and memory in animal models and humans. Faculty members investigating aging in rodent and monkey models will discuss mechanisms of synaptic and neuronal aging, what causes such changes, and potential interventions to protect against them. The aging brain is dynamic and undergoes transitions that create states of resilience or vulnerability to age-related neurodegenerative diseases. Accordingly, we will also address cognitive aging and alterations across the lifespan in humans, as well as individual variability and potential protective factors. In addition, we will consider whether the events that underlie cognitive aging are independent of those that lead to the degenerative cascade of AD or are mechanistically linked. In the process, the Advanced Course will move from molecular and cellular processes through synaptic neurobiology and plasticity, to in vivo imaging and human cognition. Inherent to the discussions will be the strengths and weaknesses of different animal models with respect to informing human health, disease, and potential therapeutics. In all cases, the methods used to obtain such data will also be highlighted to underline strengths and limitations for the participants, with respect to their own research pursuits.
John H. Morrison
Synaptic Health: Implications for Cognitive Aging
Cognitive decline with aging represents the single most important health problem facing western society as the demographics of our populations shift toward a higher representation of elderly people. While Alzheimer’s Disease (AD) remains the single largest threat in this regard, cognitive decline in the absence of frank dementia has a profound impact on the quality of life, and aging itself is the highest risk factor for AD. With respect to neurodegeneration, cortical circuitry and synaptic health, what is the difference between AD and cognitive aging? Is the latter simply a mild form of the former? Does cognitive aging lead to AD? We will discuss these issues in some detail, but the short answer is that the dementia of AD results from the massive death of key neurons that interconnect cortical areas involved with learning and memory, whereas cognitive aging results from declining synaptic health in these circuits in the absence of neuron death. The nonhuman primate (NHP) model has been particularly useful to characterize the synaptic and cellular events that underlie cognitive decline, particularly in the prefrontal cortex (PFC) which is quite similar in structure, connectivity, and function to human prefrontal cortex. Interestingly, both the “synaptic strategy” employed to perform cognitive functions and the nature of synaptic decline in PFC and hippocampus, two regions highly vulnerable to aging, differ both quantitatively and qualitatively in the NHP. For example, thin spines on pyramidal cell dendrites in PFC suffer a dramatic loss with age that is highly correlated with cognitive decline, whereas mushroom and stubby spines appear unaffected by age. The same class of highly plastic spines that is vulnerable to aging is protected by cyclical estradiol treatment, suggesting that protection against age-related decline is feasible. In addition, the density of pathologic mitochondria at PFC synapses correlates with cognitive impairment, and estradiol decreases the presence of pathologic mitochondria in synapses. Synaptic aging in the hippocampus follows a different pattern. For example, in the dentate gyrus (DG), there is minimal overall synapse loss. However, synaptic complexity decreases with age, and there appears to be an age-related failure of AMPA receptor insertion in the large, stable synapses that correlates with cognitive decline. Thus, the DG and PFC differ in the key elements of synaptic health that are vulnerable to aging, yet preserving healthy synaptic phenotypes will help preserve cognitive function. The techniques employed to link synaptic health with cognitive performance require high resolution, quantitative microscopy, and these approaches will be discussed as well.
The question of whether such synaptic changes leave these neurons vulnerable to AD in humans remains unresolved yet critically important. The interface between declining synaptic health and initiation of the degenerative cascade of AD has been very difficult to isolate and model. We are now trying to develop two NHP models of AD to address this issue, one based on amyloid toxicity and one based on tau toxicity. The methodology employed to develop these models and progress on these models to date will be discussed at the Course.
Normal Human Cognitive Aging: Maintenance Versus Loss
Human cognitive aging differs between and is malleable within individuals. In the absence of a strong genetic program, it is open to a host of hazards, such as vascular conditions, metabolic syndrome, and chronic stress, but also open to protective and enhancing factors, such as experience-dependent cognitive plasticity. Longitudinal studies suggest that leading an intellectually challenging, physically active, and socially engaged life may mitigate losses and consolidate gains, but results need to be interpreted with caution, as individuals are not randomly assigned to lifestyles. I will review some meta-mechanisms that have been suggested to promote successful cognitive aging, such as maintenance, compensation, selection, and plasticity, and argue that maintenance of brain structure and function appears to play a key role. I will underscore the need for intervention studies that give science and society a hint about what would be possible if conditions were different. Finally, I will argue that research on mechanisms regulating the onset and termination of critical periods shows that plasticity itself is plastic, and hence may open up new avenues for cognitive interventions in adulthood.
Roberta Diaz Brinton
Dynamic System Biology Transition States of the Aging Brain: Opportunities to Prevent, Delay and Treat Neurodegenerative Disease
Age is the greatest risk factor for multiple neurodegenerative diseases. In that context, the prevailing perception of the aging brain is of linear decline across multiple systems. A diametrically different perspective is that the aging brain is a dynamic adaptive organ that initiates multiple survival systems throughout the aging process. While these adaptations in the aging brain are for the majority of persons beneficial, they can, in vulnerable populations, lead to increased risk of neurodegenerative disease.
The systems biology of transition states in normal aging and neurodegeneration provides insights into mechanisms of disease risk and disease progression. Risk of multiple neurodegenerative diseases can emerge during neuroendocrine transitions of aging when gene networks undergo shifts in activation and expression. These risk networks underlie the prodromal phase of neurodegenerative disease. Later, transition states typify the progressive nature of multiple neurodegenerative diseases. Risk for and progression of Alzheimer’s disease are exemplars of both risk that can emerge during neuroendocrine transitions and the transition states of disease progression.
Synapses at the Interface of Ageing and Dementia
Ageing is the strongest risk factor for developing dementia, but the neurobiological mechanisms at play in the process of transitioning from normal healthy ageing to a pathological neurodegenerative disease state remain poorly understood. An important biological spectrum that may play a key role in this process is synaptic resilience versus synaptic degeneration during ageing. Synapse loss is the strongest pathological correlate of cognitive decline in Alzheimer’s disease, the most common form of dementia, and synaptic changes are thought to contribute to cognitive decline in non-pathological, healthy ageing. Experiments in models of Alzheimer’s disease and in human post-mortem tissue point to soluble forms of amyloid beta and tau, the proteins that aggregate in the hallmark Alzheimer’s lesions, in synapse degeneration. At the interface of ageing and dementia, we also find evidence that apolipoprotein E epsilon 4 (apoE4), contributes to synaptic degeneration. apoE4 is associated both with a higher risk of developing Alzheimer’s disease and with cognitive decline during ageing. As well as driving synapse loss, pathological proteins have recently been found to spread trans-synaptically via neural circuits. In this part of the Course, we will explore the evidence for mechanisms of synaptic pathology in Alzheimer’s disease and discuss whether synaptic resilience and cognitive reserve may be protective against age-related degeneration.
Excitatory-Inhibitory Signaling Dynamics across the Lifespan: Implications for Cognitive Decline
Memory and executive functions, supported by the medial temporal lobe and prefrontal cortex, respectively, are particularly vulnerable to decline across the lifespan. Although the neural substrates that enable long-term memory and executive functions are distinct, both require sustained excitation of pyramidal neurons as well as coordinated signaling from inhibitory interneurons that synthesize γ-aminobutyric acid (GABA). Under normal circumstances, interneurons regulate excitation of individual pyramidal cells, and synchrony in neural networks, to establish the complex network dynamics that enable cognition. This session will focus on structural, molecular and electrophysiological evidence across species that implicates altered excitatory/inhibitory (E/I) signaling in different aspects of age-associated cognitive decline. Possible causative factors for E/I signaling disruptions including stress and age-related neuropathology will be discussed, as will challenges and opportunities for pharmacological intervention. Throughout the session, we will consider approaches for effectively modeling different aspects of human cognition in rodents, including memory, executive function and decision making. Particular attention will be given to assessments that sensitively detect individual differences in cognitive function as well as those that lend themselves to within-subjects assessment for longitudinal experimental designs.
Cognitive Decline in Aging: A Neuropsychological Approach
Many, but not all, aspects of cognitive function decline across the lifespan. Although patterns of decline are evident at the population level, there are also substantial individual differences such that some elderly individuals retain cognitive abilities at high levels even until the end of their lives. A goal of research in neurobiology of aging is to uncover the mechanisms leading to preservation versus decline of cognitive ability with aging. We will discuss fundamentals of research aimed at achieving this goal, including measurement and reliability, behavioral testing issues and neuropsychological specificity, and an overview of common cognitive tests employed in a variety of species, including rodents, nonhuman primates, and humans. Special attention will be paid to two regions implicated in memory and learning that are particularly vulnerable to aging, the hippocampus and related medial temporal lobe structures, and the prefrontal cortex. We will discuss the functions and connectivity of these systems. We will emphasize issues in translation of cognitive assessments between animals and humans, and the relative benefits of different modes of research. This will provide basis for further discussion of specific neurobiological mechanisms of both “normal” cognitive aging and age-related neurodegenerative diseases, and how they may be productively studied in model systems.
Longitudinal Studies of the Aging Brain and Cognition: What Time Tells and What We Are Still Waiting to Hear
Brain and cognition change with age, and although the general trend reflects progressive declines, the rates of change differ among individuals as well as across brain regions and cognitive domains. The mechanisms underlying heterogeneity and heterochronicity of aging remain unclear. During the Course, we will examine the candidates for explaining individual variability in aging with an eye on designing effective strategies for mitigating its most egregious effects and we will survey the extant literature on brain aging in humans, with the emphasis on longitudinal studies of regional neuroanatomy. Also, the impact of vascular, metabolic, and inflammatory risk factors on the trajectories of change, as well as the influence of these factors on cognitive performance will be analyzed. Additional focus will be a model that builds on the conceptualization of aging as an expression of cumulative cellular damage inflicted by reactive oxygen species and ensuing declines in energy metabolism and we will outline the ways and means of adapting this model, Free-Radical Induced Energetic and Neural Decline in Senescence (FRIENDS), to human aging and testing it within constraints of non-invasive neuroimaging.