Brain Amyloid Deposition and the Cognition-Mobility Interface

Neelesh Nadkarni, MD, PhD, FRCPC, joined the Division of Geriatric Medicine in 2010. He is also a past scholar at the Pittsburgh Claude D. Pepper Older Americans Independence Center, and he is currently a co-investigator at the Pittsburgh Alzheimer’s Disease Research Center, which is co-directed by Drs. Oscar Lopez and William Klunk.

“Interactions between cognition and mobility are very important for older adults. Those who have problems performing two tasks simultaneously have been found in past research to exhibit an increased risk of mobility decline and falls.” 
Neelesh Nadkarni, MD, PhD, FRCPC

Dr. Nadkarni’s main research focus looks at the interaction between cognition and mobility in older adults, and how changes in the brain with aging affect this interaction. His current K23 grant from the NIA — The Aging Brain and the Cognition-Mobility Interface in Clinically Normal Older Adults — sees Dr. Nadkarni studying the application of brain imaging techniques with respect neurodegenerative disorders, small vessel disease, and amyloidosis to better understand changes in the brain as a result of aging, and their relationship to cognition and mobility.

Dr. Nadkarni also is a primary investigator or co-investigator on more than a dozen current studies, all largely related to Alzheimer’s disease, cognition, and mobility. Past published works by Dr. Nadkarni include studies on gait characterization and cognitionmobility interactions in Alzheimer’s disease, statins and brain integrity in older adults, cerebellar gray matter volumes and gait speed, interleukin-6 levels and slow gait, and others.

Dual-Tasking in Cognition and Mobility Studies

Dual-task studies, with respect to Dr. Nadkarni’s work, involve both a mental task and a physical task, done independently of one another to establish baseline results, then done in tandem. For example, walking and dialing a phone, or walking and performing a memory recall task. “There is a whole body of literature looking at dual-tasking, how completing a mental task while walking can constrain one’s performance with both tasks. However, not much is known about dual-tasking in patients with dementia, or with healthy older adults. Prior to arriving at the University of Pittsburgh, my doctoral work looked at how changes in walking affect patients with early Alzheimer’s disease compared to healthy older adults. We found that older adults — healthy patients without early Alzheimer’s disease but with amyloid deposition — have some subtle gait changes when you have them perform dual-task activities. Vascular disease changes in the brain, which happen with aging, seem to affect this interaction between performing a mental task while walking,” says Dr. Nadkarni.

Dual-task studies are an integral part of Dr. Nadkarni’s research and have led to several interesting findings in recent years. “Interactions between cognition and mobility are very important for older adults. Those who have problems performing two tasks simultaneously have been found in past research to exhibit an increased risk of mobility decline and falls. Performance on dual-task measures has been shown to predict cognitive decline and Alzheimer’s disease,” says Dr. Nadkarni.

Amyloid Deposition and Slow Gait in Cognitively Healthy Older Adults

Amyloid-b deposition in the brain is a key feature of Alzheimer’s disease. The discovery of Pittsburgh compound B (PiB) by Drs. Klunk, Mathis, and colleagues at the University of Pittsburgh has allowed for the in vivo detection and mapping of betaamyloid deposits in the brain via positron emission tomography (PET) imaging. While beta-amyloid deposition is definitively linked to Alzheimer’s disease, less is known about the effects of the protein on other physiological functions or disease processes.

Dr. Nadkarni and colleagues are actively studying the role of beta-amyloid on cognition and mobility in healthy older adults who do not have cognitive impairments or Alzheimer’s disease, but some of them have high levels of beta-amyloid deposits in the brain. This research seeks to determine the effects of amyloid accumulation on cognition and mobility, and also how changes in mobility and cognition in preclinical Alzheimer’s disease, which in otherwise healthy adults may be predictive of future clinical progression.

In their study titled Brain Amyloid-b and Slow Gait in Older Adults Without Dementia: Influence of Cognition and APOE-e4 Genotype, published in JAMA Neurology in 2017, Dr. Nadkarni and colleagues examined walking speeds in a cohort of 184 dementia free older adults, 140 of whom were cognitively normal on neuropsychological testing. These individuals also received PET scans in order to quantify the amount of beta-amyloid deposits in the brain. They found that high levels of beta-amyloid in the brain was associated with slow walking speeds in the whole cohort, but in the cognitively normal population, cognition and APOE-e4 genetic carrier status influenced this association between betaamyloid and slow walking.

In another study titled Cerebral Amyloid Deposition and Dual-tasking in Cognitively Normal, Mobility Unimpaired Older Adults, published in Journal of Gerontology Medical Sciences in 2017, Dr. Nadkarni and colleagues showed the relationship between beta-amyloid and cognitionmobility interaction measures. They used dual-tasks, which refers to performing cognitive tasks while walking, as a means to quantify the cognition-mobility interface. “In this study, these healthy older adults were cognitively normal and had no mobility impairments, with normal gait speeds and no history of falls. We then ran them through our dual-task paradigms to see if we could detect subtle changes in either gait or cognition and correlate that to the individuals who have high levels of brain amyloid,“ says Dr. Nadkarni.

At the conclusion of the study, they found that on these dual-task tests, cognitively normal older adults with higher beta-amyloid in the brain slowed down significantly more than those with low levels of brain beta-amyloid. In effect, they found that dual-task performance is not only affected in those with Alzheimer’s disease, but also in those with preclinical Alzheimer’s disease.

Practical Applications of Dual-Task Studies

PET scans are expensive. Having some kind of mechanistic test, such as dual-task mobility/cognition studies, may in the future prove useful front-line assessments to point to who may be at higher risk for developing dementia and mobility impairments, and who may benefit more from a PET scan to assess amyloid deposition. “Dual-task assessments should be able to help us target at-risk individuals for the expensive and confirmatory brain imaging tests that can detect abnormal aging related brain pathologies so that we can target these individuals early on for interventions to prevent cognitive and mobility decline,” says Dr. Nadkarni.

References and Further Reading

Nadkarni NK, Perera S, Snitz BE, Mathis CA, Price J, Williamson JD, DeKosky ST, Klunk WE, Lopez OL. Brain Amyloid-b and Slow Gait in Older Adults Without Dementia: Influence of Cognition and APOE-e4 Genotype. JAMA Neurol. 2017; 74(1): 82-90.

Nadkarni NK, Lopez OL, Perera S, Studenski SA, Snitz BE, Erickson KI, Mathis CA, Nebes RD, Redfern M, Klunk WE. Cerebral Amyloid Deposition and Dual-tasking in Cognitively Normal, Mobility Unimpaired Older Adults.J Gerontol A Biol Sci Med Sci. 2017; 72(3): 431-437.

Nadkarni NK, Nunley KA, Aizenstein H, Harris TB, Yaffe K, Satterfield S, Newman AB, Rosano C. Association Between Cerebellar Gray Matter Volumes, Gait Speed, and Information Processing Ability in Older Adults Enrolled in the Health ABC Study. J Gerontol A Biol Sci Med Sci. 2013;

Nadkarni NK, Boudreau RM, Studenski SA, Lopez OL, Liu G, Kritchevsky S, Yaffe K, Newman AB, Rosano C. Slow Gait, White Matter Characteristics, and Prior 10-year Interleukin-6 levels in Older Adults. Neurology. 2016; 87(8): 1993-1999.

Nadkarni NK, Perera S, Studenski SA, Rosano C, Aizenstein H, Van Sweringen JM. Callosal Hyperintensities and Gait Speed Gain From Two Types of Mobility Interventions in Older Adults. Arch Phys Med Rehabil. 2014;

Nadkarni NK, Perera S, Hanlon JT, Lopez OL, Newman AB, Aizenstein H, Elam M, Harris TB, Kritchevsky S, Yaffe K, Rosano C. Statins and Brain Integrity in Older Adults: Secondary Analysis of the Health ABC Study. Alzheimer’s and Dementia. 2015; 11: 12-2-1211.