ByShubhankar Kulkarni
Treatment for Age-related Macular Degeneration
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Subash Chapagain Sep 19, 2020
What are the best ways to preserve cognitive fitness with ageing?
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Is it possible to attenuate the age-associated decline in cognition?
Ageing related neurodegeneration and associated disorders are one of the major challenges for health systems all over the world. The potentially obnoxious functional effects of brain ageing include a decline in creativity and the ability to generate novel ideas, impaired executive functioning ( top-down cognitive functions involving focus and attention), decrease in openness to experience, and decreased empathy .
There is ample neurobiological evidence that justifies the functional decline in cognition and affect in the aging brain. It has been reported that there occurs a significant synaptic loss in the hippocampal region with aging that can be correlated to severity of learning impairment and cognitive loss . Moreover, at the cellular level, age-related changes in calcium transmission underlie detrimental changes in synaptic plasticity relating to functional decline in old age . Studies have also found out that the levels of dopamine receptor D1/D2R are affected by aging even though no significant reduction in dopamine synthesis is observed while aging- initiative of the fact that brain aging is related with defective post synaptic dopaminergic signaling .
The dopaminergic system is also the target of age-dependent changes that critically affect
motivation and decision-making, thereby shaping overall cognitive performance. In addition to dopaminergic aberration, it is also seen that changes in the activity and expression of metabotropic glutamate receptors (mGluRs) also plays a role in age related cognitive decline . The association between dopamine and glutamate is particularly relevant with regard to frontostriatal circuits, the neural pathways that connect frontal lobe regions with the basal ganglia (striatum) that mediate motor, cognitive, and behavioural functions.Changes in dopaminergic and glutamatergic pathways, as well as their interactions via the basal ganglia, can, therefore, affect brain plasticity.
With all of these functional, cellular and molecular mechanisms that establish the association of ageing with cognitive impairment, what could be the best ways in which we can preserve the cognitive function? Are there available approaches to enhance cognition and intelligence during old age? What can be the pharmacologic and non-pharmacological interventions?
[1]Murman DL. The Impact of Age on Cognition. Semin Hear. 2015;36(3):111-121. doi:10.1055/s-0035-1555115
[2]Geinisman Y, deToledo-Morrell L, Morrell F, Persina IS, Rossi M. Age-related loss of axospinous synapses formed by two afferent systems in the rat dentate gyrus as revealed by the unbiased stereological dissector technique. Hippocampus
[3]Norris CM, Halpain S, Foster TC. Reversal of age-related alterations in synaptic plasticity by blockade of L-type Ca2+ channels. J Neurosci. 1998;18:3171–3179.
[4]Karrer, T.M. et al. (2017) Reduced dopamine receptors and transporters but not synthesis capacity in normal aging adults: a meta-analysis. Neurobiol. Aging 57, 36–46
[5]Menard C, Quirion R. Successful cognitive aging in rats: a role for mGluR5 glutamate receptors, homer 1 proteins and downstream signaling pathways. PLoS One. 2012;7:e28666.
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Creative contributions
Physical activity
Led by the examples from the other session (https://brainstorming.com/sessions/how-do-you-jump-start-creativity-and-get-good-ideas-flowing/98), I found it necessary to mention physical activity as a way of fighting the cognitive problems in old age or disease. It has been proven that exercise helps people with impaired verbal memory and learning (https://www.hindawi.com/journals/jar/2013/861893/).
Moreover, scientists are on a trace of exciting evidence that physical activity is related to better cardiorespiratory fitness, and thus connected to the improved cognitive function of people with neurologic disorders (https://www.archives-pmr.org/article/S0003-9993(11)00086-4/pdf; https://sunwarrior.com/blogs/health-hub/improve-cognitive-function-exercise).
To make it more precise, scientists gathered papers stating that both, physical (automatic, repetitive, high energy) and motor activities (require high neuromuscular effort; etc dancing) result in positive change in cognitive functions (https://www.frontiersin.org/articles/10.3389/fmed.2019.00057/full).
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Mindful exercises
There is a loss of nerve-muscle coordination with age [1]. This loss was earlier thought to be a product of age. However, recent findings suggest that even in old age, healthy muscles are highly innervated by adjacent neurons and they do have the optimal functional capacity. Loss of nerve-muscle coordination can be minimized/ delayed by performing mindful exercises. As an example, walking or running is less mindful and does not occupy a major part of our attention. As against, performing different ladder drills is more mindful. You need to provide complete attention to the drill to do it correctly. Such exercises help strengthen your muscles and bones, while simultaneously improving cardiovascular strength and nerve-muscle coordination. Since they require your attention, they help improve cognition, too.
Here is a list of some mindful exercises:
1. Ladder drills for beginners and experts: https://www.youtube.com/watch?v=67XP-AekUoA
2. Reaction time: A simple exercise that checks your hand-eye coordination is clicking on the screen when the screen changes color - https://humanbenchmark.com/tests/reactiontime/
A more active reaction time measuring and improving activity is to catch the measuring scale mid-air dropped by another person. The mark on the scale where you caught it is your score. Lower the score, the better the reaction time.
3. Using the non-dominant hand to play catch.
4. Performing different balance poses. For advanced stages, close your eyes while performing.
5. Performing different exercises simultaneously – For example, performing squats on a balance board, hula hooping workout on a balance board, hula hooping workout weights in the hand, etc.
6. Playing target games like Darts.
Reference:
1. Staff Writer, 2018, “Muscle loss in old age linked to fewer nerve signals”, BBC Online, https://www.bbc.com/news/health-43347409 retrieved 7 June 2018
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Using combinatorial techhniques
Apart from physical and cognitive training, there can be other interventions towards cognitive enhancement:
1. Noninvasive Brain Stimulation (NIBS)
NIBS is a set of technologies and techniques that are used to modulate excitability of the brain via transcranial stimulation. Transcranial magnetic stimulation (TMS) and transcranial current stimulation (TCS) are two mainly deployed modes of NIBS (1). It has been found that NIBS can induce neuroplastic effects via dopaminergic action. Moreover, the effects of NIBS are NMDA-R-dependent, indicating that the process has an effect on cognitive processes related to attention, spatial working memory, and verbal learning and memory (2).NIBS might, therefore, be more efficient when modulating brain regions relevant for compensatory activity in the aging individuals, at least for high-performing individuals.
2. Cognitive Enhancing Drugs (CED)
Neurotransmitters can be effectively targeted so as to enhance cognitive functioning. Mainly, the following different targets can be intervened:
a) Dopaminergic Cognitive Enhancing Drug
Methylphenidate (MPD) is a dopamine inhibiting and norepinephrine transporter that acts on the brain arousal system and the cerebral cortex increasing sympathomimetic activity of the CNS. MPD administration affects functional brain connectivity and activates the regions that are involved in memory and visual attention. MPD has been also reported to increase thalamic/striatal connectivity to the hypothalamus and amygdala which are the regions for critical memory and alertness (3).
Modafinil is another non-amphetamine compound that acts as a competitive binder to the dopamine receptor as well as inhibitor of noradrenaline uptake. Preclinical evidence has shown that modafinil improves cognition, mnemonic functions, spatial planning, attention, and performance accuracy (4). This drug also elevates extracellular serotonin, glutamate, histamine and orexin concentrations and decreases gamma-amino-butyric acid (GABA) levels. Modafinil has also been linked with hippocampal neurogenesis (5) and promotion of synapsis by positively influencing Brain Derived Neurotrophic Factor (BDNF) mRNA expression (6).
b) Glutamatergic Enhancing Drugs
Ampakines (AK) are positive allosteric modulators of a subtype of ionotropic glutamate
receptors, the AMPARs. AK-driven improvement has been reported in monkeys during complex cognitive tasks that was associated with functional connectivity in the frontal and temporal cortices (7). In preclinical studies involving aging individuals, AK was seen to counteract the age-related and amyloid-dependent impairment of Long Term Potentiation (LTP) and learning (8). Moreover, AK CX456 increases neurogenesis of stem cells and counteracts age-related diminishing of dendritic branches in the cortex and hippocampus of animal models (9).
In light of this evidence, we can use synergistic approaches combining both pharmacological and non-pharmacological techniques for ageing-related cognitive enhancement.
References:
1. Nitsche, M.A. et al. (2006) Dopaminergic modulation of longlasting direct current-induced cortical excitability changes in the human motor cortex. Eur. J. Neurosci. 23, 1651–1657
2. Huang, Y.-Z. et al. (2007) The after-effect of human theta burst stimulation is NMD receptor dependent. Clin. Neurophysiol.118, 1028–1032
3. Farr, O.M. et al. (2014) The effects of methylphenidate on resting-state striatal, thalamic and global functional connectivity in healthy adults. Int. J. Neuropsychopharmacol. 17, 1177–1191
4. Battleday, R.M. and Brem, A.-K. (2015) Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: a systematic review. Eur. Neuropsychopharmacol. 25,1865–1881
5. Nagata, T. et al. Association between DNA methylation of the BDNF promoter region and clinical presentation in Alzheimer’s disease. Dement. Geriatr. Cogn. Dis. Extra 5, 64–73
6. Dell’Osso, B. et al. (2014) Wake-promoting pharmacotherapy for psychiatric disorders. Curr. Psychiatry Rep. 16, 524
7. Porrino, L.J. et al. (2005) Facilitation of task performance and removal of the effects of sleep deprivation by an ampakine (CX717) in nonhuman primates. PLoS Biol. 3, e299
8. Jurado, S. (2018) AMPA receptor trafficking in natural and pathological aging. Front. Mol. Neurosci. 10, 446
9. Dickstein, D.L. et al. (2013) Dendritic spine changes associated with normal aging. Neuroscience 251, 21–32
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...by staying positive
In a very recent 9-year longitudinal study on 991 middle-aged and older U.S. adults, scientists examined the associations between the so-called "positive affect" and memory . They found out that people who felt enthusiastic, attentive, proud, active, etc. had a significantly less memory decline across 9 years.
Because estrogen, dopamine, and serotonin account for most of the "positive emotions", it could be interesting to dig deeper into the mechanism of their action. Also, a general strategy to increase population cognitive fitness (memory, in specific) could be to lift and maintain the general "happiness" factor high. It could be done by simple "positive affect" polls over a certain period.
[1]https://www.sciencedaily.com/releases/2020/10/201029135501.htm
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Cognitive activities
Similar to physical activity, cognitive activity plays an important role in maintaining cognitive fitness in old age. Cognitive tasks should be performed regularly. They should be intended to improve/ maintain the different types of cognitive processes:
1. Sensation and perception: To improve the five commonly known senses - vision, hearing, smell, taste, and touch, playing different games is the best idea. For example, building complex Lego structures and solving puzzles improves the visual perception, and learning to play a new instrument improves your auditory perception. Apart from these commonly known senses, we have systems to perceive balance, body position and movement, pain, and temperature. Most of these can be improved by taking a stroll in the wilderness, in different terrain. Exercises, too, help in improving these senses.
2. Attention: Different games like “Track-the-ball” that is placed under the cups and the positions of the cups are interchanged, or “Spot-the-difference” between two images, or “Where’s Waldo?” help improve attention.
3. Memory: Different memory games
4. Complex cognitive abilities can be improved by playing games that nurture problem-solving, reasoning, decision-making, creative and divergent thinking, etc. Learning a new language is another way to maintain brain health. For example, games like “2048”, “Sudoku”, “Rubik’s cube”, games that involve solving mysteries, etc.
Across all these activities, novelty plays a big role. You need to move on to a different game once you think you are pretty good at it or start losing interest in it.
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