Most neurocognitive disorders manifest as a multifaceted phenotype. Both major and minor neurocognitive disorders are characterized by a triad of symptoms, including cognitive deficits (such as impaired memory, attention, and/or verbal fluency), neuropsychiatric symptoms, (an umbrella term encompassing symptoms like anxiety, depression, apathy, sleep disturbances, aggression, agitation, hallucinations, or delusions), and impaired activities of daily living (Alexopoulos et al., Reference Alexopoulos2021). In contrast to individuals with major neurocognitive disorder (known previously as dementia), in minor neurocognitive disorder (including mild cognitive impairment) cognitive deficits are not severe enough to affect basic activities of daily living, more complex activities, however, may be impaired (such as managing finances or managing the household) (Perneczky et al., Reference Perneczky2006). Interestingly, neuropsychiatric symptoms are not only present in advanced neurocognitive disorders but also occur in mild or even preclinical disease stages, increasing risk for (further) cognitive decline (Burhanullah et al., Reference Burhanullah2020). Anxiety and depression symptoms in older adults have exacerbated during the current COVID-19 pandemic crisis and seem to pertain to loneliness and decreased physical activity, two consequences of COVID-19 containment measures (e.g. social distancing and movement restrictions) (Creese et al., Reference Creese2020). Of note, behavioral changes exert negative effects on the quality of life both of patients and caregivers (Schumann et al., Reference Schumann, Alexopoulos and Perneczky2019).
Physical exercise programs, a common type of non-pharmacological interventions, provide a viable strategy for the treatment and prevention of neurocognitive disorder, for which no causal therapies are available yet. Potentially protective lifestyle factors to ameliorate the risk of (further) cognitive decline in older adults are attracting increased attention. The 2019 World Health Organization (WHO) guidelines on risk reduction of cognitive decline and dementia advocated physical activity and a healthy lifestyle as important prevention strategies (Risk Reduction of Cognitive Decline and Dementia, 2019). In this context, the term physical exercise commonly refers to 6-month interventions of moderate-intensity aerobic physical activity for a minimum of 30 min, 5 days/week or rigorous-intensity aerobic activity for a minimum of 20 min, 3 days/week (La Rosa et al., Reference de La Rosa2020), while the effects of resistance training occurring at least twice a week for 6 months have also been investigated. Physical exercise programs are frequently coupled with cognitive training, or aerobic physical activity is combined with resistance training (La Rosa et al., Reference de La Rosa2020).
Mounting evidence points to the beneficial effects of physical exercise on cognitive function and on decelerating cognitive decline. Global cognition appears to benefit from physical exercise interventions, according to the observations of intervention trials and a recent meta-analysis (Falck et al., Reference Falck, Davis, Best, Crockett and Liu-Ambrose2019). Nonetheless, the contribution of changes in specific cognitive domains to the observed improvement of global cognition is still elusive (Lautenschlager et al., Reference Lautenschlager, Cox and Ellis2019). In particular, no final conclusions have been drawn with regard to the impact of physical exercise interventions on memory, cognitive processing speed, visuospatial ability, attention and executive functions, a broad term encompassing planning and problem-solving capability. Of note, no differences were detected between the impact of aerobic and resistance physical training on cognition, while combining aerobic with resistance training may provide the greatest benefit for cognitive health (Falck et al., Reference Falck, Davis, Best, Crockett and Liu-Ambrose2019). The possible additional cognitive effect of combined cognitive and physical exercise interventions compared to just physical exercise warrants further investigation (Karssemeijer et al., Reference Karssemeijer, Aaronson, Bossers, Smits, Olde Rikkert and Kessels2017).
Evidence is also accumulating on the beneficial effects of physical exercise on another key aspect of neurocognitive disorder, that is, neuropsychiatric symptoms, posing a heavy burden to both patients and caregivers. Particularly during the current COVID-19 pandemic crisis, low activity levels may represent a modifiable target for resilience and management programs of neuropsychiatric symptoms (Creese et al., Reference Creese2020). Kouloutbani et al. (Reference Kouloutbani, Venetsanou, Markati, Karteroliotis and Politis2021) reviewed critically trials examining the effects of exercise interventions on neuropsychiatric symptoms. They placed particular emphasis on delineating the specific characteristics of the physical exercise intervention (type, frequency, intensity, and duration) that was implemented in each considered study. Their results elaborate on the role of physical exercise as secondary prevention approach for individuals with minor neurocognitive disorder and as a tertiary preventative approach for patients with major neurocognitive disorder (Lautenschlager, Reference Lautenschlager2014). Relying on both the “Preferred Reporting Items for Systematic Review and Meta-Analyses-PRISMA” guidelines for systematic reviews and the study trial quality assessment CONSORT 2010 checklist, they scrutinized randomized controlled trials based on seven aerobic interventions, one resistance/strength program and five programs combining strength, balance, and flexibility exercises. The considered trials lasted between 2 and 15 months and included 1,557 individuals with neurocognitive disorder who completed the respective experimental procedures. The results were analyzed and synthesized according to the type of exercise applied in the trials. The quality of the reported results ranged between 8.5/25 and 21.5/25, reflecting the number of individual items on the 25-item CONSORT checklist that were satisfactorily reported in each study, with higher scores indicating a higher degree of compliance with the guidelines. Repetitive aerobic exercise three to five times a week was found to exert a positive effect on neuropsychiatric symptoms, while multidimensional interventions and the combination of different types of exercises did not seem to be as effective. Of note, strength training programs, applied three times a week, were found to significantly reduce depression and behavioral problems in patients with impaired mobility who performed wheelchair-bound resistance band exercises. Exercise appears to have the greatest effect in aberrant motor behavior, depression, apathy, and agitation (Kouloutbani et al., Reference Kouloutbani, Venetsanou, Markati, Karteroliotis and Politis2021). Despite the clear indication that exercise, and especially aerobic exercise may be effective in the management of neuropsychiatric symptoms, the methodological heterogeneity of the studies impedes the development of specific practical recommendations for daily routine implementation of such interventions. Such a step seems inevitable, in order to reduce or ideally even minimize the treatment of older adults with neurocognitive disorders with potentially harmful drugs such as antipsychotics, antidepressants, and benzodiazepines, requiring careful consideration of the risk–benefit ratio in older individuals (Bessey and Walaszek, Reference Bessey and Walaszek2019; Gustafsson et al., Reference Gustafsson, Sandman, Karlsson, Gustafson and Lövheim2013).
Besides the positive influence of physical exercise on cognitive function and neuropsychiatric symptoms in neurocognitive disorder, positive effects on activities of daily living were also observed (Groot et al., Reference Groot2016; Karssemeijer et al., Reference Karssemeijer, Aaronson, Bossers, Smits, Olde Rikkert and Kessels2017). The findings of recent meta-analyses corroborate moderate-to-large effects of physical exercise on its own or combined with cognitive training on activities of daily living in older adults (Groot et al., Reference Groot2016; Karssemeijer et al., Reference Karssemeijer, Aaronson, Bossers, Smits, Olde Rikkert and Kessels2017). Preserving activities of daily living is of high clinical and economic relevance, since functional disability results in increased dependency in daily life, lower quality of life, higher caregivers’ burden (Schumann et al., Reference Schumann, Alexopoulos and Perneczky2019), and higher long-term costs (Karssemeijer et al., Reference Karssemeijer, Aaronson, Bossers, Smits, Olde Rikkert and Kessels2017).
The effects of physical exercise on the different symptoms of neurocognitive disorders have a biological foundation, counteracting or mitigating the chronic neurodegenerative processes; compensatory psychological mechanisms may in addition play a role, particularly in the case of neuropsychiatric symptoms. The beneficial effects of physical exercise interventions are underpinned by morphological, cellular, and molecular changes linked but not restricted to angiogenesis, neurogenesis, synaptogenesis, higher neural efficacy, amelioration of inflammation, and stimulation of neurotrophic factors that enhance learning, memory, and brain plasticity. These changes result in reduced neurodegenerative and vascular disease burden, stimulation of the immune system, increased release of neurotrophins, and regional gray matter expansion (Suo et al., Reference Suo2016), thereby protecting vulnerable brain regions and alleviating cerebral blood flow reduction. Interestingly, biological effects (such as upregulation of functional connectivity between strategic brain regions) are present even 12 months after intervention cessation and these long-term effects seem to be distinct from the within-intervention biological changes (Broadhouse et al., Reference Broadhouse2020). Furthermore, the beneficial effect of physical activity interventions on cognition and sleep quality may reduce perceived feelings of weakness, subsequently leading to lower levels of stress, irritability, aggression, apathy, and depression (Kouloutbani et al., Reference Kouloutbani, Venetsanou, Markati, Karteroliotis and Politis2021). Moreover, the attenuation of caregivers burden, another positive consequence of exercise interventions, possibly pertains to higher patience and tolerance of neuropsychiatric symptoms and to more positive and constructive behaviors toward the patient, minimizing caregiver attitudes that could provoke exacerbation of such symptoms (Kouloutbani et al., Reference Kouloutbani, Venetsanou, Markati, Karteroliotis and Politis2021).
The mounting evidence on the beneficial effects of physical exercise interventions on different symptoms of neurocognitive disorder forms a reliable basis for producing a blueprint for a feasible strategy to incorporate such interventions into the routine therapeutic repertoire. Physical exercise interventions increasingly become part of the therapeutic schedule of dementia day-care centers and nursing homes and recently home-based workouts (including endurance, resistance, and balance exercises; app-based exercise training with online partners), and outdoor activities have been recommended in order to overcome the negative consequences of home confinement and social isolation during the current COVID19 pandemic crisis (Müller et al., Reference Müller, Achraf, Zou, Apfelbacher, Erickson and Müller2020). Nonetheless, there remain open questions on the optimal implementation of such strategies in everyday clinical practice. For instance, studies with sizeable samples and detailed and rigorous multi-arm design comparing the effects of single physical training, single cognitive training, combined cognitive and physical training, multicomponent interventions incorporating physical exercise, cognitive training, savoring, gratitude and engagement in value-based activities (Treichler et al., Reference Treichler2020), and a control group are urgently needed, in order to compare the therapeutic effects of the different types of intervention. Light should also be shed on optimal duration, frequency, intervention type, and mode of combination of the constituent parts of the intervention for older individuals with neurocognitive disorder and different demographic characteristics, mobility, and physical health status. Moreover, long-term effects of interventions particularly on neuropsychiatric symptoms are largely unknown and need further investigation. Another only marginally addressed issue of high clinical significance concerns the influence of physical exercise interventions on the use and doses of antipsychotics in adults with neurocognitive disorder. Clear answers may enable a personalized, optimal, modality-specific exercise dosing and catalyze the incorporation of guidelines for tailoring personalized physical activity programs meeting the individual needs of older individuals with neurocognitive disorder into clinical recommendations.
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Most neurocognitive disorders manifest as a multifaceted phenotype. Both major and minor neurocognitive disorders are characterized by a triad of symptoms, including cognitive deficits (such as impaired memory, attention, and/or verbal fluency), neuropsychiatric symptoms, (an umbrella term encompassing symptoms like anxiety, depression, apathy, sleep disturbances, aggression, agitation, hallucinations, or delusions), and impaired activities of daily living (Alexopoulos et al., Reference Alexopoulos2021). In contrast to individuals with major neurocognitive disorder (known previously as dementia), in minor neurocognitive disorder (including mild cognitive impairment) cognitive deficits are not severe enough to affect basic activities of daily living, more complex activities, however, may be impaired (such as managing finances or managing the household) (Perneczky et al., Reference Perneczky2006). Interestingly, neuropsychiatric symptoms are not only present in advanced neurocognitive disorders but also occur in mild or even preclinical disease stages, increasing risk for (further) cognitive decline (Burhanullah et al., Reference Burhanullah2020). Anxiety and depression symptoms in older adults have exacerbated during the current COVID-19 pandemic crisis and seem to pertain to loneliness and decreased physical activity, two consequences of COVID-19 containment measures (e.g. social distancing and movement restrictions) (Creese et al., Reference Creese2020). Of note, behavioral changes exert negative effects on the quality of life both of patients and caregivers (Schumann et al., Reference Schumann, Alexopoulos and Perneczky2019).
Physical exercise programs, a common type of non-pharmacological interventions, provide a viable strategy for the treatment and prevention of neurocognitive disorder, for which no causal therapies are available yet. Potentially protective lifestyle factors to ameliorate the risk of (further) cognitive decline in older adults are attracting increased attention. The 2019 World Health Organization (WHO) guidelines on risk reduction of cognitive decline and dementia advocated physical activity and a healthy lifestyle as important prevention strategies (Risk Reduction of Cognitive Decline and Dementia, 2019). In this context, the term physical exercise commonly refers to 6-month interventions of moderate-intensity aerobic physical activity for a minimum of 30 min, 5 days/week or rigorous-intensity aerobic activity for a minimum of 20 min, 3 days/week (La Rosa et al., Reference de La Rosa2020), while the effects of resistance training occurring at least twice a week for 6 months have also been investigated. Physical exercise programs are frequently coupled with cognitive training, or aerobic physical activity is combined with resistance training (La Rosa et al., Reference de La Rosa2020).
Mounting evidence points to the beneficial effects of physical exercise on cognitive function and on decelerating cognitive decline. Global cognition appears to benefit from physical exercise interventions, according to the observations of intervention trials and a recent meta-analysis (Falck et al., Reference Falck, Davis, Best, Crockett and Liu-Ambrose2019). Nonetheless, the contribution of changes in specific cognitive domains to the observed improvement of global cognition is still elusive (Lautenschlager et al., Reference Lautenschlager, Cox and Ellis2019). In particular, no final conclusions have been drawn with regard to the impact of physical exercise interventions on memory, cognitive processing speed, visuospatial ability, attention and executive functions, a broad term encompassing planning and problem-solving capability. Of note, no differences were detected between the impact of aerobic and resistance physical training on cognition, while combining aerobic with resistance training may provide the greatest benefit for cognitive health (Falck et al., Reference Falck, Davis, Best, Crockett and Liu-Ambrose2019). The possible additional cognitive effect of combined cognitive and physical exercise interventions compared to just physical exercise warrants further investigation (Karssemeijer et al., Reference Karssemeijer, Aaronson, Bossers, Smits, Olde Rikkert and Kessels2017).
Evidence is also accumulating on the beneficial effects of physical exercise on another key aspect of neurocognitive disorder, that is, neuropsychiatric symptoms, posing a heavy burden to both patients and caregivers. Particularly during the current COVID-19 pandemic crisis, low activity levels may represent a modifiable target for resilience and management programs of neuropsychiatric symptoms (Creese et al., Reference Creese2020). Kouloutbani et al. (Reference Kouloutbani, Venetsanou, Markati, Karteroliotis and Politis2021) reviewed critically trials examining the effects of exercise interventions on neuropsychiatric symptoms. They placed particular emphasis on delineating the specific characteristics of the physical exercise intervention (type, frequency, intensity, and duration) that was implemented in each considered study. Their results elaborate on the role of physical exercise as secondary prevention approach for individuals with minor neurocognitive disorder and as a tertiary preventative approach for patients with major neurocognitive disorder (Lautenschlager, Reference Lautenschlager2014). Relying on both the “Preferred Reporting Items for Systematic Review and Meta-Analyses-PRISMA” guidelines for systematic reviews and the study trial quality assessment CONSORT 2010 checklist, they scrutinized randomized controlled trials based on seven aerobic interventions, one resistance/strength program and five programs combining strength, balance, and flexibility exercises. The considered trials lasted between 2 and 15 months and included 1,557 individuals with neurocognitive disorder who completed the respective experimental procedures. The results were analyzed and synthesized according to the type of exercise applied in the trials. The quality of the reported results ranged between 8.5/25 and 21.5/25, reflecting the number of individual items on the 25-item CONSORT checklist that were satisfactorily reported in each study, with higher scores indicating a higher degree of compliance with the guidelines. Repetitive aerobic exercise three to five times a week was found to exert a positive effect on neuropsychiatric symptoms, while multidimensional interventions and the combination of different types of exercises did not seem to be as effective. Of note, strength training programs, applied three times a week, were found to significantly reduce depression and behavioral problems in patients with impaired mobility who performed wheelchair-bound resistance band exercises. Exercise appears to have the greatest effect in aberrant motor behavior, depression, apathy, and agitation (Kouloutbani et al., Reference Kouloutbani, Venetsanou, Markati, Karteroliotis and Politis2021). Despite the clear indication that exercise, and especially aerobic exercise may be effective in the management of neuropsychiatric symptoms, the methodological heterogeneity of the studies impedes the development of specific practical recommendations for daily routine implementation of such interventions. Such a step seems inevitable, in order to reduce or ideally even minimize the treatment of older adults with neurocognitive disorders with potentially harmful drugs such as antipsychotics, antidepressants, and benzodiazepines, requiring careful consideration of the risk–benefit ratio in older individuals (Bessey and Walaszek, Reference Bessey and Walaszek2019; Gustafsson et al., Reference Gustafsson, Sandman, Karlsson, Gustafson and Lövheim2013).
Besides the positive influence of physical exercise on cognitive function and neuropsychiatric symptoms in neurocognitive disorder, positive effects on activities of daily living were also observed (Groot et al., Reference Groot2016; Karssemeijer et al., Reference Karssemeijer, Aaronson, Bossers, Smits, Olde Rikkert and Kessels2017). The findings of recent meta-analyses corroborate moderate-to-large effects of physical exercise on its own or combined with cognitive training on activities of daily living in older adults (Groot et al., Reference Groot2016; Karssemeijer et al., Reference Karssemeijer, Aaronson, Bossers, Smits, Olde Rikkert and Kessels2017). Preserving activities of daily living is of high clinical and economic relevance, since functional disability results in increased dependency in daily life, lower quality of life, higher caregivers’ burden (Schumann et al., Reference Schumann, Alexopoulos and Perneczky2019), and higher long-term costs (Karssemeijer et al., Reference Karssemeijer, Aaronson, Bossers, Smits, Olde Rikkert and Kessels2017).
The effects of physical exercise on the different symptoms of neurocognitive disorders have a biological foundation, counteracting or mitigating the chronic neurodegenerative processes; compensatory psychological mechanisms may in addition play a role, particularly in the case of neuropsychiatric symptoms. The beneficial effects of physical exercise interventions are underpinned by morphological, cellular, and molecular changes linked but not restricted to angiogenesis, neurogenesis, synaptogenesis, higher neural efficacy, amelioration of inflammation, and stimulation of neurotrophic factors that enhance learning, memory, and brain plasticity. These changes result in reduced neurodegenerative and vascular disease burden, stimulation of the immune system, increased release of neurotrophins, and regional gray matter expansion (Suo et al., Reference Suo2016), thereby protecting vulnerable brain regions and alleviating cerebral blood flow reduction. Interestingly, biological effects (such as upregulation of functional connectivity between strategic brain regions) are present even 12 months after intervention cessation and these long-term effects seem to be distinct from the within-intervention biological changes (Broadhouse et al., Reference Broadhouse2020). Furthermore, the beneficial effect of physical activity interventions on cognition and sleep quality may reduce perceived feelings of weakness, subsequently leading to lower levels of stress, irritability, aggression, apathy, and depression (Kouloutbani et al., Reference Kouloutbani, Venetsanou, Markati, Karteroliotis and Politis2021). Moreover, the attenuation of caregivers burden, another positive consequence of exercise interventions, possibly pertains to higher patience and tolerance of neuropsychiatric symptoms and to more positive and constructive behaviors toward the patient, minimizing caregiver attitudes that could provoke exacerbation of such symptoms (Kouloutbani et al., Reference Kouloutbani, Venetsanou, Markati, Karteroliotis and Politis2021).
The mounting evidence on the beneficial effects of physical exercise interventions on different symptoms of neurocognitive disorder forms a reliable basis for producing a blueprint for a feasible strategy to incorporate such interventions into the routine therapeutic repertoire. Physical exercise interventions increasingly become part of the therapeutic schedule of dementia day-care centers and nursing homes and recently home-based workouts (including endurance, resistance, and balance exercises; app-based exercise training with online partners), and outdoor activities have been recommended in order to overcome the negative consequences of home confinement and social isolation during the current COVID19 pandemic crisis (Müller et al., Reference Müller, Achraf, Zou, Apfelbacher, Erickson and Müller2020). Nonetheless, there remain open questions on the optimal implementation of such strategies in everyday clinical practice. For instance, studies with sizeable samples and detailed and rigorous multi-arm design comparing the effects of single physical training, single cognitive training, combined cognitive and physical training, multicomponent interventions incorporating physical exercise, cognitive training, savoring, gratitude and engagement in value-based activities (Treichler et al., Reference Treichler2020), and a control group are urgently needed, in order to compare the therapeutic effects of the different types of intervention. Light should also be shed on optimal duration, frequency, intervention type, and mode of combination of the constituent parts of the intervention for older individuals with neurocognitive disorder and different demographic characteristics, mobility, and physical health status. Moreover, long-term effects of interventions particularly on neuropsychiatric symptoms are largely unknown and need further investigation. Another only marginally addressed issue of high clinical significance concerns the influence of physical exercise interventions on the use and doses of antipsychotics in adults with neurocognitive disorder. Clear answers may enable a personalized, optimal, modality-specific exercise dosing and catalyze the incorporation of guidelines for tailoring personalized physical activity programs meeting the individual needs of older individuals with neurocognitive disorder into clinical recommendations.