The Ageing Brain

Functional decline may result from synaptic changes rather than neuronal loss and the altered regulation of adult neurogenesis.

A synopsis of recent studies at the molecular, cellular and functional level illustrates normal senescence demonstrates adaptation and plasticity rather than inevitable decline.

Introduction

Studies with ageing humans and animals have demonstrated that higher levels of fitness are correlated with executive functions associated with frontal lobe and hippocampal brain regions brain.

Research suggests that both general and process-specific declines occur in a variety of perceptual, cognitive and action-related processes during the course of normal aging.

Older adults typically perform more poorly than young adults in terms of both response latency and accuracy on tasks as diverse as perceptual speed, working memory, tracking, decision-making, explicit memory and multiple task processing.

The vascular component of the brain response may be driven by physical activity whereas the neuronal component may reflect learning.

Recent results have implicated neurogenesis, at least in the hippocampus, as a component of the brain response to exercise, with learning enhancing survival of these neurons.

Non-neuronal tissues also respond to experience in the mature brain, indicating that the brain reflects both its recent and longer history of experience.

• Normal senescence versus neurological pathology
• No widespread neural death.
• Homeostatic control versus Progressive deregulation.
• Apoptosis

Programmed cell death is the underlying mechanism of neural plasticity. Synaptic turnover is the selective removal of dysfunctional neurons and glia. However, there is evidence that loss is minimal in normal senescence.

Inflammation

Occurs during acute phase injury in which debris from dying cells is removed as well as exudates such as amyloids. (Lucin & Wyss-Coray, 2009) &

Inflammation can impair growth factor signaling, exacerbate the metabolic syndrome and accelerate cognitive decline. However,  this can be reduced by exercise. (Cotman, Berchtold & Christie, 2007).

Generation of free radicals

This is what causes oxidative stress, however this and inflammation are a necessary immune protection system for brain functioning. (Lucin & Wyss-Coray, 2009)

Strain Bad for Brain – Another great reason to avoid chronic distress.

by Robert W. Lash, M.D. published online July 13, 2007

Genetic Factors

APOE-e4 allele

Brain Anatomy

Entorhinal Cortex & Primary Visual Cortex

Minimal volume reduction or stable with age.

Perforant path which connects the entorhinal cortex to the dentate gyrus.

This area receives multiple inputs from multiple neocortical areas and provides major output to the hippocampus and associated areas. Neurological diseases begin by affecting the entorhinal cortex which in turn impair hippocampal involvement in memory.

Medial Temporal Lobe

Lateral Prefrontal Cortex

Volume reduction with age.

Hippocampus

Volume reduction with age (Jessberger & Gage, 2008).

Normal ageing has minimal structural effects on the hippocampus and adjacent Medial Temporal Lobe, although age-related functional changes might affect circuits that involve interactions between the PFC and the hippocampus, thereby causing age-related decrements in memory function that is mediated by hippocampal neurons.

Layer II in Cortex

Increase of neurofibrillary tangles witnessed in normal population over 55 years of age.

Molecular and Cellular Level

Neurochemical Phenotype

Study cell class or neural circuit to see if there are changes in the pattern distribution. It is possible that subtle changes at this level rather than cell loss leads to compromised behavioural function.

The study of individual neurons may provide the answer. For example, spine density decreases with age but there is no cell death. It may be a change in dendrites or receptors.

Intervention – Exercise

Synaptogenesis

Neurogenesis

Glial Plasticity

Glial cells are primed by low­grade chronic inflammation which may lead to changes in intercellular crosstalk. This may contribute to susceptibility to neurodegeneration. (Bertini, Colavito, Tognoli, Seke Etet & Bentivoglio, 2010).

Vascular Plasticity

Exercise initiates growth factor cascades, a mechanism that mediates the effects of stimulating cognition, synaptic plasticity, neurogenesis and improving cerebrovascular perfusion. IGF-1 signaling converges on BDNF signaling. (Cotman, Berchtold & Christie, 2007).

Exercise reduces peripheral risk factors for cognitive decline such as hypertension and insulin resistance, components of the metabolic syndrome that increase the risk for neurodegeneration and brain dysfunction.

Research

Investigations of normal senescence have been dominated by pathology models. Ageing is examined with neuroimaging techniques and a convergence of animal brain plasticity and human cognitive studies of aging. It raises the issue of selective vulnerability.

Animal Studies

Rats and the Hippocampus

Enhanced hippocampal neurogenesis is a reproducible effects of exercise in the rodent brain and this may illustrate the key mechanism mediating exercise-related improvements in cognitive function.

Exercise stimulates proliferation of the neural progenitor population, increases the number of new neurons, and promotes survival of these new cells.

New neurons are functionally integrated into the hippocampal architecture [van Praag, H. et al., 2002. Functional neurogenesis in the adult hippocampus. Nature 415, 1030–1034.], but they are unique from mature granule cells in that they have a lower threshold of excitability [Schmidt-Hieber, C. et al. (2004) Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus. Nature, 429,184–187)]. This feature makes these new neurons well suited to mediate exercise-stimulated enhanced plasticity, such as facilitated perforant-path LTP [Farmer, J. et al. (2004) Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague–Dawley rats in vivo.Neuroscience 124, 71-77.].

Rat studies that show long term potentiation in the hippocampus. (Boric, Munoz, Gallagher & Kirkwood, 2008)

Hippocampal neurogenesis has been linked to learning and memory although its functional consequences are still uncertain.

Human Studies

Observational Studies

Observational studies suggest that physical activity can have a neuroprotective effect on later life cognition, however, causation cannot be established.

Cite meta-analysis (Kramer)

Longitudinal Studies

Longitundinal data from epidemiological studies provide another source of converging evidence to predict cognitive improvements or maintenance from exercise some years later. One study [3], with over a thousand participants, was to predict cognitive change, as indexed by a composite cognitive measure that included language, verbal and non-verbal memory, conceptualization, and visuospatial tests, over a 2.5 years period in adults between the ages of 70 and 79. Interestingly, a number of measures of cardiorespiratory fitness and general physical activity level also served as strong predictors of cognitive vitality for this population.

Randomised Clinical Trials

A number of randomized intervention studies have examined the relationship between exercise and cognitive function.

A randomized controlled trial has shown that regular physical activity prevents dementia, but recent RCTs suggests an improvement of cognitive functioning in persons involved in aerobic programs, and evidence is accumulating from basic research.

A recent meta-analysis of randomized controlled trials indicated that aerobic exercise training confers modest improvements in neurocognitive function, specifically in attention and processing speed, executive function, and memory in healthy older adults. Aerobic exercise did not appear to benefit working memory (Smith, Blumenthal, Hoffman, Cooper, Strauman, Welsh-Bohmer, Browndyke & Sherwood, 2010).

Brain Imaging

Age-related differences in patterns of brain activation have been established through the use of PET and fMRI. In a variety of cognitive operations including attention, multi-task processing and task switching, linguistic processing, and aspects of working and long-term memory.

Differences in dedifferentiation [CH1] between young and old.

References

• Bertini, G., Colavito, V., Tognoli, C., Seke Etet, P.F. & Bentivoglio, M., (2010). The aging brain, neuroinflammatory signaling and sleep-wake regulation. Italian Journal of Anatomy and Embryology, 115, No. 1, 31-38.
• Boric, K., Munoz, P., Gallagher, M. & Kirkwood, A. (2008) Potential Adaptive Function for Altered Long-Term Potentiation Mechanisms in Aging Hippocampus. The Journal of Neuroscience, 28(32), 8034-8039.
• Burke, S.N. & Barnes, C.A. (2006). Neural plasticity in the ageing brain. Nature 32, Vol. 7,
• Colcombe, S. & Kramer, A.F. (2003) Fitness Effects on the Cognitive Function of Older Adults: A Meta-Analytic Study. Psychological Science 14, No. 2, 125-130.
• Cotman, C.W., Berchtold, N.C. & Christie, L., (2007). Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends in Neurosciences, 30 (9), 464-471.
• Jessberger, S & Gage F.H., (2008). Stem Cell-associated structural and functional plasticity in the aging hippocampus. Psychological Aging, 23(4), 684–691.
• Kramer, A. F., Erickson, K. I. & Colcombe, S.J., (2006) Neural Changes Associated with Training Exercise, cognition, and the aging brain. Journal of Applied Physiology 101: 1237–1242.
• Lucin K.M. & Wyss-Coray, T., (2009) Immune activation in brain aging and neurodegeneration: too much or too little? Neuron, 64(1), 110–122.
• Rolland, Y., Abellan van Kan, G. & Vellas, B. (2010) Healthy Brain Aging: Role of Exercise and Physical Activity
• Smith, P.J., Blumenthal, J.A., Hoffman, B.M., Cooper, H., Strauman, T.A., Welsh-Bohmer, K., Browndyke, J.N. & Sherwood, A., (2010). Aerobic Exercise and Neurocognitive Performance: a MetaAnalytic Review of Randomized Controlled Trials. Psychosomatic Medicine, 72(3), 239-252.