# Exercise as it relates to Disease/Cardiorespiratory Fitness: is it the answer to reduce brain atrophy in early-stage Alzheimer’s Disease?

The following is a journal article analysis of Cardiorespiratory Fitness and Brain Atrophy in Early Alzheimer’s Disease.

## What is the background to this research?

Alzheimer's Disease (AD) is a progressive irreversible neurodegenerative process resulting in the incidence of dementia. From the 47 million people living with dementia worldwide and with over 9.9 new cases every year, AD effects approximately 70% of this population.
AD results in the brain cell death and shrinking of the cortex involved in memory, language and judgement. The outer surface of the brain is affected first, developing symptoms of short-term memory loss before the damage spreads to deeper areas of the brain leading to increasingly severe memory loss, disorientation and behaviour changes.
The greatest risk factor in the incidence of AD is aging, with the majority of morbidity cases over the age of 65. This makes early diagnosis of AD essential and although treatments cannot stop its ongoing effects, there are worldwide efforts to slow the severe progressive symptoms and improve quality of life.
There have been numerous studies on the positive effects of physical fitness in reducing structural and functional changes that occur in a normal aging population however, less is known of its effects in pathological brain states. Whether exercise and fitness can influence the neurodegenerative effects of AD have produced mixed results and fundamentally remains unknown. One such effort undertaken by Jeffrey M. Burns, et. al. (2008) looked to uncover on the role of cardiorespiratory fitness in reducing brain atrophy associated with early-stage AD.

## Where is the research from?

Research was conducted at the University of Kansas (KU), USA, in the School of Medicine, the Hohlund Brain Imaging Centre, and the Energy Balance Laboratory and Centre for Physical Activity, Nutrition and Weight Management. The corresponding author of the journal article, Jeffrey M. Burns, is a Professor in Neurology at KU, the co-director of the KU Alzheimer’s Disease Centre, and has been involved in AD clinical research for over 13 years. Grants were received from the National Institutes of Aging, the National Institute on Neurological Disorders and Stroke, the National Institutes of Health, and KU.

## What kind of research was this?

A cross-sectional study was performed examining cardiorespiratory fitness in relation to brain structure and cognition in individuals with early-stage AD against a nondemented control group. As the cross-sectional design is a type of observational study, it can be recognised as level II or III evidence with randomised controlled trials considered level I evidence, based on the methodological quality of design, validity, and applicability.

## What did the research involve?

Participants completed the following assessments:

##### Clinical Assessment

Included standard physical and neurological assessments, a semi-structured interview and a determination of subject’s Clinical Dementia Rating (CDR) in which a score of 0 considered nondemented, and 0.5 or 1 representing early-stage AD.

##### Neuropsychological Assessment

Administered several mental tests as a way of determining global cognitive performance.1 Tests included standard measures of memory, language, verbal fluency and visuospatial ability.

##### Cardiorespiratory Fitness

Using a symptom-limited graded treadmill test and a non-rebreathing facemask, VO2peak was determined and normalised by lean mass to use as a primary fitness measure.

##### Physical Activity and Frailty Assessment

Habitual physical activity was estimated using the Physical Activity Scale in the Elderly (PASE), which assessed physical activity within the last week.1 Physical frailty was assessed using a Physical Performance Test, which consisted of timed physical tasks.

##### Neuroimaging

A structural MRI scan of the brain provided detailed gross anatomy and brain volume.1 Total intracranial volume was normalised as a percentage to minimise gender differences and estimate brain atrophy.
Why the methodology was the best approach:
Participants were excluded from the study if they showed any condition other than AD that may impair the study’s completion and applicability. Further, the CDR method has a diagnostic accuracy of 93% in determining the presence and severity of AD. The PASE method was developed specifically for older individuals making it the most valid and reliable approach as a measure of physical activity.
Limitations:
The self-structured interview could be considered unreliable as AD subject’s that are prone to memory loss may have difficulty remembering fine details. The use of a cross-sectional study design has been acknowledged as a limitation in the interpretation and single cause of the results found. The authors also noted that assessing cardiorespiratory VO2peak at only one point in time may limit its validity and reliability.

## What were the basic results?
##### Important findings

* AD subjects had a lower cardiorespiratory fitness than their nondemented counterparts
* Higher fitness levels were associated with an increased brain volume in those with early-stage AD
* VO2peak was associated with a better performance in delayed memory
* Global cognitive performance was associated with whole brain volume however, this was primarily driven by age as opposed to fitness
| | Nondemented (n=64) | Early AD (n=57) |
| Age (years) | 72.7 (6.3) | 74.3 (6.7) |
| Whole Brain Volume (%ICV) | 78.2 (2.8) | 75.6 (3.3) |
| VO2peak by Lean Mass (ml/kg/min) | 38.1 (6.3) | 34.7 (5.0) |
ICV = intracranial volume
One single cause of the associations found could not be determined due to the use of a cross-sectional design. Instead, three interpretations were determined:
* Cardiorespiratory fitness reduces AD-related brain atrophy
* Cardiorespiratory fitness declines due to the onset of AD
* An underlying factor modifies AD-related brain atrophy and cardiorespiratory fitness
The author’s implications of the findings were that the data should be considered cautiously to reduce any misinterpretation of the results and further research is required to develop more valid evidence.

## What conclusions can we take from this research?

The results conclude that although cardiorespiratory fitness was shown to have a correlation with whole brain volume, further research is required to uncover a clear moderator of AD-related brain atrophy. Although fitness seems to play a role in cognitive performance and reduced memory loss, it seems that age is still a defining factor in the neurodegenerative process associated with AD.

##### Can the interpretation of results be aligned with other research in the area?

Animal studies suggest that higher fitness levels are associated with elevated growth factors important for memory. Fitness has also been reported to enhance learning and mediate neurodegeneration in AD mouse models. Additionally, AD may not only affect the brain but have a more widespread systemic influence including mitochondrial dysfunction, and metabolic and biochemical abnormalities. As VO2peak is a determinant of metabolic activity, its established correlation with brain atrophy suggests metabolic dysfunction occurring with AD, a possible interest for future investigation.

## Practical advice

It is implied that this research can be used as practical advice and have real-world implications, however, there are a number of considerations to outline before conducting any exercise intervention for elderly AD patients:
* Conduct a pre-exercise screening tool to assess fitness, general health and activity levels of the participant as well as the incidence of any other conditions the patient may have.
* Motivation is essential in the long-term sustainability of an exercise program
* Patient may have poor memory requiring patience and clarity from the prescriber

## Further information/resources

* Alzheimer's Australia: https://www.fightdementia.org.au
* Alzheimer's Disease Fact Sheet: https://www.nia.nih.gov/health/alzheimers-disease-fact-sheet
* Exercise and physical activity recommendations for AD sufferers: https://www.alzheimers.org.uk/info/20029/daily_living/15/exercise_and_physical_activity
* Exercise prescription for patients with AD: http://www.humankinetics.com/excerpts/excerpts/exercise-programming-for-patients-with-alzheimers-disease

## References

* 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Burns, J. M; Cronk, B. B; Anderson, H. S; Donnelly, J. E; Thomas, G. P; Harsha, A; Brooks, W. M; Swerdlow, R. H (2008). "Cardiorespiratory fitness and brain atrophy in early Alzheimer disease". Neurology. 71 (3): 210–6. doi:10.1212/01.wnl.0000317094.86209.cb. PMC 2657657. PMID 18625967.
* 1 2 3 Alzheimer's Disease & Dementia | Alzheimer's Association [Internet]. Alz.org. 2017 [cited 14 September 2017]. Available from: http://www.alz.org/alzheimers_disease_what_is_alzheimers.asp
* 1 2 3 Alzheimer's Australia | Alzheimer's disease [Internet]. Fightdementia.org.au. 2017 [cited 14 September 2017]. Available from: https://www.fightdementia.org.au/about-dementia/types-of-dementia/alzheimers-disease
* ↑ Dementia [Internet]. World Health Organization. 2017 [cited 14 September 2017]. Available from: http://www.who.int/mediacentre/factsheets/fs362/en/
* ↑ Jeffrey Burns, M.D., M.S. [Internet]. Kumc.edu. 2017 [cited 15 September 2017]. Available from: http://www.kumc.edu/school-of-medicine/neurology/faculty/jeffrey-burns-md-ms.html
* ↑ GSU Library Research Guides: Literature Reviews: Types of Clinical Study Designs [Internet]. Research.library.gsu.edu. 2017 [cited 15 September 2017]. Available from: http://research.library.gsu.edu/c.php?g=115595&p=755213
* ↑ Song, Jae W; Chung, Kevin C (2010). "Observational Studies: Cohort and Case-Control Studies". Plastic and Reconstructive Surgery. 126 (6): 2234–42. doi:10.1097/PRS.0b013e3181f44abc. PMC 2998589. PMID 20697313.
* ↑ Research Hub: Evidence Based Practice Toolkit: Levels of Evidence [Internet]. Libguides.winona.edu. 2017 [cited 15 September 2017]. Available from: http://libguides.winona.edu/c.php?g=11614&p=61584
* ↑ Neeper, S. A; Góauctemez-Pinilla, F; Choi, J; Cotman, C (1995). "Exercise and brain neurotrophins". Nature. 373 (6510): 109. Bibcode:1995Natur.373..109N. doi:10.1038/373109a0. PMID 7816089.
* ↑ Cotman, C; Berchtold, N. C (2002). "Exercise: A behavioral intervention to enhance brain health and plasticity". Trends in Neurosciences. 25 (6): 295–301. doi:10.1016/S0166-2236(02)02143-4. PMID 12086747.
* ↑ Adlard, P. A; Perreau, V. M; Pop, V; Cotman, C. W (2005). "Voluntary Exercise Decreases Amyloid Load in a Transgenic Model of Alzheimer's Disease". Journal of Neuroscience. 25 (17): 4217–21. doi:10.1523/JNEUROSCI.0496-05.2005. PMID 15858047.
* ↑ Van Praag, H; Shubert, T; Zhao, C; Gage, F. H (2005). "Exercise Enhances Learning and Hippocampal Neurogenesis in Aged Mice". Journal of Neuroscience. 25 (38): 8680–5. doi:10.1523/JNEUROSCI.1731-05.2005. PMC 1360197. PMID 16177036.
* ↑ Swerdlow, Russell H; Kish, Stephen J (2002). "Mitochondria in Alzheimer's disease". In Sharma, Hari S.; Sharma, Aruna (eds.). Mitochondrial Function and Dysfunction. International Review of Neurobiology. Vol. 53. pp. 341–85. doi:10.1016/S0074-7742(02)53013-0. ISBN 978-0-12-366854-7.
* ↑ Bruel, Arlette; Cherqui, Gisèle; Columelli, Simone; Margelin, Dominique; Roudier, Michel; Sinet, Pierre-Marie; Prieur, Marguerite; Pérignon, Jean-Louis; Delabar, Jean (1991). "Reduced protein kinase C activity in sporadic Alzheimer's disease fibroblasts". Neuroscience Letters. 133 (1): 89–92. doi:10.1016/0304-3940(91)90064-Z. PMID 1792001.
* ↑ Brown, Deborah; Spanjers, Katie; Atherton, Nicky; Lowe, Janet; Stonehewer, Louisa; Bridle, Chris; Sheehan, Bart; Lamb, Sarah E (2015). "Development of an exercise intervention to improve cognition in people with mild to moderate dementia: Dementia and Physical Activity (DAPA) Trial, registration ISRCTN32612072". Physiotherapy. 101 (2): 126–34. doi:10.1016/j.physio.2015.01.002. PMID 25724322.