Pain and the Prognosis for Dementia

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While researchers are busy developing sophisticated laboratory tests to predict who will eventually succumb to Alzheimer’s disease, a seemingly mundane observation may provide one of the strongest predictors yet identified: pain.

Pharmacology of aging why age matters

Molly Zimmerman from the Albert Einstein College of Medicine summarized research implicating pain as a risk factor for dementia and Alzheimer’s disease at a symposium last year at the New York Academy of Sciences entitled, The Pharmacology of Aging: Why Age Matters.

Discussing her work with the Einstein Aging Study in the Bronx, NY, she reported that pain is prevalent among the elderly, with nearly 50% reporting the experience of some level of pain on a daily basis. However, when pain becomes intense enough to prevent normal activities, a condition termed “pain interference,” the risks of developing new-onset dementia double. Furthermore, pain is associated with reduced hippocampal volume as measured by structural MRI and a reduction in the ratio of N-acetylaspartate to creatine (NAA/Cr) as measured by MRS, a marker of hippocampal integrity [1]. Reductions in both hippocampal volume and NAA/Cr ratio are associated with diminished cognitive function [2].

Pain is a complex and highly subjective experience, and it is unclear precisely how pain interferes with cognition. Previous studies suggest that pain modulates brain networks involved in attention [3], which are necessary for both cognition and pain perception. In another report, treatment of chronic pain was observed to improve cognition and reverse brain abnormalities, in this case the thinning of certain areas of the prefrontal cortex [4].

Dementia patients are typically under-treated for pain [5], and there was once debate regarding whether dementia patients experience pain in the same manner as non-demented subjects. For example, frontotemporal dementia patients are reported to have an elevated pain threshold and tolerance as measured by changes in fMRI [6], and there have been case reports of dementia patients who were seemingly oblivious to horrific lesions or injuries [7]. However, others report no reductions in fMRI measured activities of pain pathways in subjects with dementia [8].

Kunz et al. measured multiple readouts of pain including subjective assessment, facial response (using a facial action coding system, FACS), motor reflex (using the nociceptive flexion reflex), and autonomic measures (sympathetic skin response, heart rate) in response to noxious stimuli, and although subjects with dementia reported similar subjective pain ratings as those reported by control subjects, their facial responses were greater and the threshold for their motor reflex was decreased compared to control subjects (their autonomic response, in contrast, was reduced) [9]. Their results suggest that the experience of pain in the dementia patient may be more intense than is reported by the patient.


  1. Zimmerman et al. Hippocampal correlates of pain in healthy elderly adults: a pilot study. Neurology. 2009 Nov 10;73(19):1567-70. doi: 10.1212/WNL.0b013e3181c0d454.
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  2. Zimmerman et al. Hippocampal neurochemistry, neuromorphometry, and verbal memory in nondemented older adults. Neurology. 2008 Apr 29;70(18):1594-600. doi: 10.1212/ Epub 2008 Mar 26.
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  3. Seminowicz and Davis. Pain enhances functional connectivity of a brain network evoked by performance of a cognitive task. J Neurophysiol. 2007 May;97(5):3651-9. Epub 2007 Feb 21.
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  4. Seminowicz et al. Effective treatment of chronic low back pain in humans reverses abnormal brain anatomy and function. J Neurosci. 2011 May 18;31(20):7540-50. doi: 10.1523/JNEUROSCI.5280-10.2011.
    View abstract
  5. Plooij et al. Pain medication and global cognitive functioning in dementia patients with painful conditions. Drugs Aging. 2012 May 1;29(5):377-84. doi: 10.2165/11630850-000000000-00000.
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  6. Carlino et al. Pain perception and tolerance in patients with frontotemporal dementia. Pain. 2010 Dec;151(3):783-9. doi: 10.1016/j.pain.2010.09.013. Epub 2010 Oct 8.
    View abstract
  7. Fisher-Morris and Gellatly. The experience and expression of pain in Alzheimer patients. Age Ageing. 1997 Nov;26(6):497-500.
    View abstract
  8. Cole et al. Pain sensitivity and fMRI pain-related brain activity in Alzheimer’s disease. Brain. 2006 Nov;129(Pt 11):2957-65. Epub 2006 Sep 2.
    View abstract
  9. Kunz et al. Influence of dementia on multiple components of pain. Eur J Pain. 2009 Mar;13(3):317-25. doi: 10.1016/j.ejpain.2008.05.001. Epub 2008 Jun 17.
    View abstract
About the Author

Robert Martone is a scientist at St. Jude Children's Research Hospital focused on neuro-oncology biomarker research.