Mood, Movement, and Memory

Mood, Movement, and Memory: an Age-related Neurodegenerative Complex?

Lotta Granholm, Heather Boger, and Marina Emborg

Aging has been associated with an increased risk of developing depression (Late Life Depression, LLD) and neurodegenerative diseases. Both Alzheimer's disease (AD) and Parkinson's disease (PD) are associated with increased risk for depression, and other commonalities such as similar risk factors, age and gender distribution. Furthermore, as AD and PD progress, it becomes evident that their symptoms are not limited to one neurotransmitter system. Because of these findings, investigators have started to investigate the possibility of a biological and/or clinical connection between the triad of symptoms (emotion, cognition and movement). Clinical studies have shown that there is a strong connection between cognitive and movement impairment (or disorders) in aged individuals. In a presentation by Jeffrey Hausdorff (Harvard University, MA), it was demonstrated that when older adults were presented with a dual task (walking and cognition) and were offered to get help with one of the tasks, they tended to first choose a walking aid rather than a memory aid. Further, patients with AD were more likely to have stride alterations when asked to perform dual tasks, and patients with early PD demonstrated freezing in pedaling or walking exercises when presented with a simple cognitive task. These overlapping functional deficits are interesting, but there is currently no concerted effort to explore this phenomenon in an organized manner, either in clinical or basic science studies.

What are some of the physiological processes leading to these age-related altered brain functions? It is well known from animal and human studies that movement disorders and memory loss associated with aging have some of the same pathological hallmarks, but starting in different brain regions and involving different neuronal circuits. Among the best described are: protein aggregation, oxidative stress, microglial activation and specific neurotransmitter loss (see Figure below). There are also life-style factors that can affect the aging brain and have severe implications for normal everyday function, such as sleep disturbances, sedentary lifestyle, high blood pressure, metabolic syndrome, obesity, and diabetes. Studies have shown that all of the above can be considered risk factors for both AD and PD. All of these are unfortunate side effects of modern society, undoubtedly leading to a surge in these diseases in future aged generations.

To summarize, it is clear that mood, cognition, and motor functions are all affected by the basic aging process, and are at least partially the result of similar processes. Future studies need to take into consideration these co-morbidities, both in the human population as well as developing relevant animal models.  There is an imminent need for more standardized animal models, both in regards to movement and cognitive testing. For example, when investigating an animal model for PD, it would be more valuable to examine not only movement behavior but also the effects of depletions and/or treatment paradigms on cognitive and, if possible, mood parameters such as motivation. Most often, studies on animal models of Parkinson's disease do not include analysis of memory performance or attention/motivation even though dopamine has strong effects on working memory, and many patients with PD undergo significant decline in cognitive function.

Age-related neurodegenerative complex can be caused by a number of different factors, isolated or in combination. While aging itself is the most common denominator, oxidative stress, inflammation, and protein aggregation are all part of the common pathology seen in PD and AD patients. Studies on movement disorders or memory loss with aging should include at least minimal studies on the other modalities described as well (and listed above in this figure), to reach further understanding of this common co-morbidity in the aged population. For example, most animal models for PD are not tested for cognitive loss or loss of motivation or attention, studies that would definitely add to the validity for future clinical treatment and for more successful drug development.