Aerobic Activity in the Healthy Elderly Is Associated with Larger Plasticity in Memory Related Brain Structures and Lower Systemic Inflammation

So your doctor needs to find out EXACTLY what the exercises and amounts of aerobic exercise are needed to get these benefits.   Not doing so is worth a call to the president of the stroke hospital asking why they haven't set proper goals for the members of the stroke department.
http://journal.frontiersin.org/article/10.3389/fnagi.2016.00319/full

Jan-Willem Thielen^1,2*, Christian Kärgel^3†, Bernhard W. Müller^4,5, Ina Rasche⁴, Just Genius^1,6, Boudewijn Bus⁷, Stefan Maderwald², David G. Norris^1,2, Jens Wiltfang⁸ and Indira Tendolkar^1,2,4,7

• ¹Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, Netherlands
• ²Erwin L. Hahn Institute for Magnetic Resonance Imaging, University of Essen-Duisburg, Essen, Germany
• ³Division of Forensic Psychiatry, Department of Psychiatry, Psychotherapy and Preventive Medicine, LWL-University Hospital Bochum, Bochum, Germany
• ⁴Department for Psychiatry and Psychotherapy, LVR-Hospital Essen, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany
• ⁵Department of Psychology, University of Wuppertal, Wuppertal, Germany
• ⁶AbbVie Neuroscience Development, Ludwigshafen, Germany
• ⁷Department of Psychiatry, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
• ⁸Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany

Cognitive abilities decline over the time course of our life, a process, which may be mediated by brain atrophy and enhanced inflammatory processes. Lifestyle factors, such as regular physical activities have been shown to counteract those noxious processes and are assumed to delay or possibly even prevent pathological states, such as dementing disorders. Whereas the impact of lifestyle and immunological factors and their interactions on cognitive aging have been frequently studied, their effects on neural parameters as brain activation and functional connectivity are less well studied. Therefore, we investigated 32 healthy elderly individuals (60.4 ± 5.0 SD; range 52–71 years) with low or high level of self-reported aerobic physical activity at the time of testing. A higher compared to a lower level in aerobic physical activity was associated with an increased encoding related functional connectivity in an episodic memory network comprising mPFC, thalamus, hippocampus precuneus, and insula. Moreover, encoding related functional connectivity of this network was associated with decreased systemic inflammation, as measured by systemic levels of interleukin 6.

Introduction

It is a well-known phenomenon that our neurocognitive abilities change with age but there are remarkable differences in the timing and trajectory of these changes (Hedden and Gabrieli, 2004; Hofer and Alwin, 2008). Investigating the effects of lifestyle factors may be highly informative for the development of interventions to reduce or delay age-related cognitive decline. Among these lifestyle factors physical exercise both enhances and preserves cognitive function in the elderly (Dustman et al., 1984; Colcombe and Kramer, 2003; Smith et al., 2010; Bherer et al., 2013). Additionally, physical exercise appears to significantly reduce the risk of adults developing dementing diseases in later years (Laurin et al., 2001; Hamer and Chida, 2009; Middleton et al., 2010; Llamas-Velasco et al., 2015). Even patients already suffering from mild cognitive impairment or dementing disorders improve in cognitive functioning after a physical exercise intervention (Heyn et al., 2004; Lautenschlager et al., 2008). Hence, physical exercise is a promising low-cost treatment to improve neurocognitive function that is accessible to most elderly.

There is general agreement that memory performance declines from early to late adulthood, and that such age-related memory impairments do not involve every domain of Memory (Grady and Craik, 2000). Decrements are typically slight in implicit memory tasks, immediate memory tasks, and in many recognition memory tasks (Grady and Craik, 2000). In contrast, age-related memory losses are substantial in episodic memory tasks involving cued or free recall (Anderson and Craik, 2000; Balota et al., 2000; Grady and Craik, 2000; Nyberg et al., 2012). In this regard, it has been shown that episodic memory (Chalfonte and Johnson, 1996; Naveh-Benjamin, 2000; Naveh-Benjamin et al., 2003, 2004), and in particular the memory for face-name or face occupation associations (Naveh-Benjamin et al., 2004; James et al., 2008; Hayes et al., 2015), is markedly reduced in the elderly. However, recent elderly studies have shown that the engagement in physical activity can counteract those episodic memory losses (Zlomanczuk et al., 2006; Hayes et al., 2015). For instance, Hayes et al. (2015) showed that engagement in physical activity, is positively associated with performance on the face-name association task. However, the neuronal correlates of this effect in terms of brain activation and functional connectivity have not yet studied. Sperling et al. (2003) examined the pattern of brain activation during the encoding of face-name associations in young and elderly. The authors showed that elderly, compared to young adults, have greater activation in parietal regions but less activation in both superior and inferior prefrontal cortices and the hippocampus, a brain region known to be essential in episodic memory (Burgess et al., 2002). One may hypothesize that engagement in aerobic physical activities has a positive effect on these brain regions affecting encoding related brain activation in and functional connectivity between these brain regions. Anatomically, the hippocampus is strongly connected to prefrontal regions as medial prefrontal cortex (mPFC; Preston and Eichenbaum, 2013) which, in turn, have reciprocal connections to several thalamic nuclei that are indirectly or directly reciprocally connected to the hippocampus in monkey (Aggleton et al., 2011). Moreover, a recent fMRI study revealed functional connectivity between hippocampus, mPFC and thalamus during episodic memory retrieval in young adults (Thielen et al., 2015). Therefore, we hypothesize that face association learning (encoding) is associated with the hippocampal-thalamus-mPFC axis and that engagement in aerobic physical activity has a positive effect on activation and functional connectivity within this memory network.

There is evidence that aerobic physical activity is associated with reduced systemic inflammation (Elosua et al., 2005; Autenrieth et al., 2009). There is also evidence that age related episodic memory decline is associated with inflammation (Simen et al., 2011). An association between inflammation and memory impairment has been reported in both, rodents, and human studies (Heyser et al., 1997; Gemma et al., 2005; Barrientos et al., 2006, 2009; Hilsabeck et al., 2010; Simen et al., 2011; Harrison et al., 2014, 2015). Thus, there seems to be an interaction between physical activity, inflammation and aging related memory decline. In this regard, it has been reported that inflammation affects the functioning of the hippocampus. For instance, peripheral injection of the bacteria Escherichia coli – leading to increased inflammation – produces both retrograde and anterograde amnesia in 24 month old, but not 3-month-old rats for memories that depend on the hippocampus (Barrientos et al., 2006). Recent studies in human have linked hippocampal activation and functional connectivity to systemic inflammation (Harrison et al., 2014, 2015). It was shown that induced (S. typhi vaccination) inflammation causes a reduced medial temporal cortex glucose metabolism and selectively impaired spatial episodic, but not procedural, memory (Harrison et al., 2014). Moreover, induced inflammation blocked functional connectivity between the substantia nigra and hippocampus that occurred during novelty processing in noninflammatory states (Harrison et al., 2015). Thus, it seems that inflammation has pronounced effects on hippocampus both, in terms activation and connectivity. Therefore, we assume that inflammation is inversely related to encoding related activation and functional connectivity within the hippocampal-thalamus-mPFC axis. Interleukin-6 (IL-6) has been recognized as an active player in inflammation (Rincon, 2012). IL-6 is both an anti-inflammatory and pro-inflammatory cytokine and can be released from different cell types as for instance astrocytes, muscle or fat cells (Gruol and Nelson, 1997; Nybo et al., 2002). IL-6 released from muscle tissue during or immediately after a bout of exercise exert anti-inflammatory effects by suppressing pro-inflammation factors. For instance, elevations in skeletal muscle derived IL-6 trigger an anti-inflammatory cascade by lowering the release of pro-inflammatory cytokines (e.g., IL-1β) via the stimulation of their antagonistic receptors (Nimmo et al., 2013). Moreover, exercise-related IL-6 triggers the release of IL-10, an anti-inflammatory molecule, which directly inhibits the synthesis of different pro-inflammatory mediators, particularly of the monocytic lineage, such as TNF-α, IL-1α, IL-1β, IL-8, and macrophage inflammatory protein-1α (Petersen and Pedersen, 2005) At rest, the release of IL-6 from skeletal muscle is minimal, with the majority being produced from adipose tissue and leucocytes, which is thought of as pro-inflammatory (Fischer, 2006; Nimmo et al., 2013). Moreover, studies revealed that regular engagement in physical activities is associated with lower systemic IL-6 levels at rest. For instance, Elosua et al. (2005) reported a negative relation between interleukin-6 to both physical fitness and leisure time related physical activity in the elderly. Lower levels of the pro-inflammatory IL-6 may reduce the risk of adults developing neurodegenerative diseases (Laurin et al., 2001; Hamer and Chida, 2009; Middleton et al., 2010; Llamas-Velasco et al., 2015). For instance, IL-6-treated hippocampal neurons showed tau hyperphosphorylation (Quintanilla et al., 2004), a hallmark of Alzheimer’s disease. Moreover, neurons subjected to chronic IL-6 treatment exhibit increased sensitivity to NMDA receptor mediated neurotoxicity (Qiu et al., 1998). In addition, it has been shown that IL-6 can have negative effects on synaptic plasticity. For instance IL-6 affects synaptic plasticity in the CA1 region of the hippocampus by causing a marked decrease in the expression of long term potentiation (LTP), the cellular model of learning and memory (Gruol and Nelson, 1997; Tancredi et al., 2000). However, we should note that IL-6 has not only destructive but also a beneficial potential. In this regard, numerous studies provide evidence for an IL-6 involvement in neuronal survival, protection, and differentiation (Hirota et al., 1996; Gadient and Otten, 1997; März et al., 1997; Loddick et al., 1998).

In the light of the aforementioned findings, we hypothesized that aerobic physical activity does not only improve episodic memory (Hayes et al., 2015) but that this effect goes along with changed brain activation and connectivity in the hippocampal-thalamus-PFC axis which in turn is inversely related to inflammation as measured with systemic IL-6 at rest. Therefore, this cross sectional study examined the effects of aerobic physical activity engagement on the performance on a face association task and related brain activation and functional connectivity in the elderly. Moreover, we hypothesized that systemic IL-6 levels are reduced in individuals that engage in aerobic physical activity which in turn is related to the functional effects, especially those that are related to the hippocampus.