Latest Research News
Link found between chronic inflammation and Alzheimer's gene risk
Data from the Framingham Heart Study has found carriers of the ApoE4 gene were much more likely to develop Alzheimer’s if they also had chronic low-grade inflammation. Indeed, the researchers suggest that, in the absence of inflammation, there might be no difference of Alzheimer's risk between ApoE4 and non-ApoE4 carriers.
Mid- to late-life increases in chronic inflammation age brain
Data from 1,532 participants in a long-running study, in which participants were tested five times every 3 years (on average), found that those who showed increasing inflammation had greater abnormalities in the brain's white matter structure.
90 people transitioned from low to persistently elevated C-reactive protein during midlife, indicating increasing inflammation. Their brains appear similar to that of a person 16 years older, researchers estimate.
Common causes of chronic inflammation include cardiovascular disease, heart failure, diabetes, high blood pressure and infections such as hepatitis C or HIV.
61% of participants were women, and 28% were African-American. At the final visit, participants were an average age of 76.
(2018). Association of Chronic Low-grade Inflammation With Risk of Alzheimer Disease in ApoE4 CarriersChronic Low-grade Inflammation and Risk of Alzheimer Disease in ApoE4 CarriersChronic Low-grade Inflammation and Risk of Alzheimer Disease in ApoE4 Carriers.
JAMA Network Open. 1(6), e183597 - e183597.
(2018). The association of mid-to late-life systemic inflammation with white matter structure in older adults: The Atherosclerosis Risk in Communities Study.
Neurobiology of Aging. 68, 26 - 33.
A pilot study involving 22 breast cancer patients currently receiving chemotherapy (mean age 54), has found that those with higher levels of inflammatory biomarkers did significantly worse on tests for short-term visual memory. One particular biomarker — tumor necrosis factor-alpha (as reflected through its two soluble receptors, TNFRI and TNFRII) — was the strongest indicator of cognitive problems.
The findings are consistent with an earlier study involving 174 breast cancer patients evaluated before chemotherapy, which found that higher levels of those biomarkers were associated with worse memory, and another study of 49 patients, which found that higher levels of sTNFRII were associated with more memory complaints after chemotherapy.
Cognition was assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB), looking at those domains previously reported to be affected in cancer survivors: visual memory, executive functioning, attention, verbal memory, and cognitive processing.
Almost all the patients were Caucasian and college-educated.
Williams, AnnaLynn M. et al. 2018. Associations between inflammatory markers and cognitive function in breast cancer patients receiving chemotherapy. Journal of Neuroimmunology, 314, 17-23. Full text available at https://www.jni-journal.com/article/S0165-5728(17)30198-4/fulltext
Patel, S.K., Wong, A.L., Wong, F.L., Breen, E.C., Hurria, A., Smith, M. et al. 2015. Inflammatory biomarkers, comorbidity, and neurocognition in women with newly diagnosed breast cancer. J. Natl. Cancer Inst., 107.
Ganz, P.A., Bower, J.E., Kwan, L., Castellon, S.A., Silverman, D.H., Geist, C. et al. 2013. Does tumor necrosis factor-alpha (TNF-alpha) play a role in post-chemotherapy cerebral dysfunction?. Brain Behav. Immun., 30, S99–108.
Unplanned hospitalizations accelerate cognitive decline in older adults
Data from the Rush Memory and Aging Project has found that emergency and urgent hospitalizations are associated with an increased rate of cognitive decline in older adults.
Non-elective hospitalizations were associated with an approximately 60% acceleration in the rate of cognitive decline from before hospitalization. Elective hospitalizations, however, were not associated with acceleration in the rate of decline at all.
Of the 930 participants (average age 81), 613 were hospitalized at least once over an average of almost five years of observation. Of those who were hospitalized, 260 (28%) had at least one elective hospital admission, and 553 (60%) had at least one non-elective hospital admission. These groups included 200 participants (22%) who had both types of hospitalizations.
The data was presented at the Alzheimer's Association International Conference in London on July 17.
Inflammation triggered by brain's own immune cells behind post-surgical decline
There is growing evidence that inflammation might be responsible for the cognitive decline seen in many older adults after surgery. Now a mouse study provides evidence that brain inflammation and cognitive decline following surgery are triggered by the brain's microglia.
When mice had their microglia temporarily depleted before surgery, they didn’t show any cognitive decline several days after surgery. They also had much lower levels of inflammatory molecules in the hippocampus. Controls — those not receiving the experimental drug to deplete microglia to around 5% of normal levels — did typically show a drop in cognitive performance.
Microglia levels returned to normal within two days after the treatment was stopped, and there was no sign of any impairment in surgical wound healing as a result of the intervention.
Delirium in older patients after surgery linked to long-term cognitive decline
A 3-year study looking at short-term and long-term cognitive decline in older patients following a surgery found that those who experienced delirium after the surgery showed significantly greater decline than those who didn’t suffer such post-surgical confusion.
The study involved 560 patients (70+), of whom 134 experienced delirium. Both groups showed a significant cognitive decline at one month, followed by a return to their previous level of cognitive function at two months and then a gradual decline for the next 34 months. However, the rate of decline over the three year follow-up was not significant for those who hadn’t experienced delirium.
Those who suffered delirium also had significantly lower cognitive function before surgery.
The odd finding that even the delirium group recovered their cognitive function at two months, before once again declining, suggests that something about the delirium triggers a cascade of events which leads to progressive, long-lasting effects.
Who’s more likely to develop delirium after surgery?
Delirium after surgery can lead to long-term cognitive decline in older adults — but not always. So what makes the difference?
A preliminary study involving 126 older adults suggests the answer lies in their cognitive function before surgery. Their global cognition score explained the most variation, with other significant factors including: IQCODE score, cognitive independent activities of daily living impairment, living alone, cerebrovascular disease, Charlson comorbidity index score, and exhaustion level. Taken together, these factors explained 32% of the variation in people’s outcome.
Delirium, an acute state of confusion, is a common condition affecting up to 50% of hospitalized older adults.
Certain leisure activities may reduce post-surgical delirium among older adults
A study of 142 older adults who underwent elective surgery found that greater participation in cognitive activities was linked with a lower incidence and lower severity of delirium.
Nearly a third of the patients (average age 71) developed post-operative delirium. Those who did had participated in fewer leisure activities before surgery compared with people who didn't experience delirium.
Out of all the activities, reading books, using email, and playing computer games reduced the risk of delirium. Playing computer games and singing were the only two activities that predicted lower severity of delirium.
The protection afforded was dose-dependent, with each additional leisure activity reducing post-operative delirium by 8%.
(2017). Microglia mediate postoperative hippocampal inflammation and cognitive decline in mice.
JCI Insight. 2(7),
(2016). The short-term and long-term relationship between delirium and cognitive trajectory in older surgical patients.
Alzheimer's & Dementia: The Journal of the Alzheimer's Association. 12(7), 766 - 775.
(Submitted). Prediction of Long-term Cognitive Decline Following Postoperative Delirium in Older Adults.
The Journals of Gerontology: Series A.
(2016). Cognitive Reserve and Postoperative Delirium in Older Adults.
Journal of the American Geriatrics Society. 64(6), 1341 - 1346.
A study involving 65 older adults (average age 66), of whom 35 had type 2 diabetes, has found that after two years, those with diabetes had decreases in their ability to regulate blood flow in the brain, and a reduced ability to regulate blood flow was associated with lower cognitive scores.
Specifically, at the start of the study those with diabetes scored an average 46 points on a cognitive test, compared with 55 in the control group. After two years, the diabetics' scores had fallen to an average of 41, while the scores of the control group hadn't fallen at all.
Greater decreases in blood flow regulation were also associated with higher levels of inflammation.
It's suggested that inflammation impairs blood flow regulation, and this accelerates cognitive decline.
Chung, C.-C., Pimentel, D., Jor’dan, A. J., Hao, Y., Milberg, W., & Novak, V. (2015). Inflammation-associated declines in cerebral vasoreactivity and cognition in type 2 diabetes. Neurology, 85(5), 450–458. http://doi.org/10.1212/WNL.0000000000001820
As we all know, people are living longer and obesity is at appalling levels. For both these (completely separate!) reasons, we expect to see growing rates of dementia. A new analysis using data from the long-running Framingham Heart Study offers some hope to individuals, however.
Looking at the rate of dementia during four distinct periods in the late 1970s, late 1980s, 1990s, and 2000s, using data from 5205 older adults (60+), the researchers found that there was a progressive decline in the incidence of dementia at a given age, with an average reduction of 20% per decade since the 1970s (22%, 38%, and 44% during the second, third, and fourth epochs, respectively).
There are two important things to note about this finding:
- the decline occurred only in people with a high school education and above
- the decline was more pronounced with dementia caused by vascular diseases, such as stroke.
The cumulative risk over five years, adjusted for age and gender, were:
- 3.6 per 100 persons during the first period (late 1970s and early 1980s)
- 2.8 per 100 persons during the second period (late 1980s and early 1990s)
- 2.2 per 100 persons during the third period (late 1990s and early 2000s)
- 2.0 per 100 persons during the fourth period (late 2000s and early 2010s).
Part of the reason for the decline is put down to the decrease in vascular risk factors other than obesity and diabetes, and better management of cardiovascular diseases and stroke. But this doesn't completely explain the decrease. I would speculate that other reasons might include:
- increased mental stimulation
- improvements in lifestyle factors such as diet and exercise
- better health care for infectious and inflammatory conditions.
The finding is not completely unexpected. Recent epidemiological studies in the U.S., Canada, England, the Netherlands, Sweden and Denmark have all suggested that “a 75- to 85-year-old has a lower risk of having Alzheimer’s today than 15 or 20 years ago.” Which actually cuts to the heart of the issue: individual risk of dementia has gone down (for those taking care of their brain and body), but because more and more people are living longer, the numbers of people with dementia are increasing.
(2016). Incidence of Dementia over Three Decades in the Framingham Heart Study.
New England Journal of Medicine. 374(6), 523 - 532.
Growing research has implicated infections as a factor in age-related cognitive decline, but these have been cross-sectional (comparing different individuals, who will have a number of other, possibly confounding, attributes). Now a large longitudinal study provides more evidence that certain chronic viral infections could contribute to subtle cognitive deterioration in apparently healthy older adults.
The study involved 1,022 older adults (65+), who had annual evaluations for five years. It revealed an association between cognitive decline and exposure to several viruses: cytomegalovirus (CMV), herpes simplex (HSV 2), and the protozoa Toxoplasma gondii.
More specifically, the IgG levels for HSV-2 were significantly associated with baseline cognitive scores, while the IgG levels for HSV-2 (genital herpes), TOX (which has been much in the news in recent years for being harbored in domestic cats, and being implicated in various neurological disorders), and CMV (a common virus which unfortunately rarely causes symptoms), but not HSV-1 (the cold sore virus), were significantly associated with greater temporal cognitive decline that varied by type of infection.
More research is obviously needed to determine more precisely what the role of different infectious agents is in cognitive decline, but the findings do point to a need for a greater emphasis on preventing and treating infections. They also add to the growing evidence that age-related cognitive decline isn't 'normal', but something that occurs when other health-related factors come into play.
(2015). Temporal Cognitive Decline Associated With Exposure to Infectious Agents in a Population-based, Aging Cohort:.
Alzheimer Disease & Associated Disorders. 1.
A six-week study involving 619 cancer patients has found that those who took part in a simple home-based exercise program significantly reduced their cognitive impairment ('chemo-brain'). The EXCAP (Exercise for Cancer Patients) was developed by the researchers some years ago, and this evaluation was a phase III randomized study for early-stage chemotherapy patients. Half the group were given standard care (no exercise during chemotherapy), while the others were given instruction to walk daily and carry out low-to-moderate resistance band training for 10 minutes, 5 days a week.
This very modest increase in exercise (the 'no-exercise' group walked on average 3,800 steps a day, while the excap group walked on average 5,000 steps) had significant effects:
- lower levels of inflammation
- less brain 'fogginess'
- fewer memory problems
- greater mobility.
Exercisers who received chemotherapy in 2-week cycles reported the greatest benefits, compared to other timing cycles.
The findings were presented at the American Society of Clinical Oncology (ASCO) annual meeting on June 1, by Karen Mustian.
A new study shows that a combination of inflammation and hypoxia activates microglia in a way that persistently weakens the connection between neurons, contributing to brain damage in conditions such as stroke and Alzheimer's disease.
(2014). Microglial CR3 Activation Triggers Long-Term Synaptic Depression in the Hippocampus via NADPH Oxidase.
Neuron. 82(1), 195 - 207.
A mouse study has found that obese mice had high levels of interleukin 1 in both their blood and their brains, and this was associated with:
- high levels of inflammation,
- low levels of a biochemical important to synapse function, and
- impaired cognitive function.
Moreover, when fat was removed from the obese mice, interleukin levels dropped dramatically, and cognitive performance improved.
Putting obese mice on an exercise program had a similar effect, even though they didn’t lose weight — but they gained muscle and lost fat.
Caffeine has been associated with a lower of developing Alzheimer's disease in some recent studies. A recent human study suggested that the reason lies in its effect on proteins involved in inflammation. A new mouse study provides more support for this idea.
In the study, two groups of mice, one of which had been given caffeine, were exposed to hypoxia, simulating what happens in the brain during an interruption of breathing or blood flow. When re-oxygenated, caffeine-treated mice recovered their ability to form a new memory 33% faster than the other mice, and the caffeine was observed to have the same anti-inflammatory effect as blocking interleukin-1 (IL-1) signaling.
Inflammation is a key player in cognitive impairment, and IL-1 has been shown to play a critical role in the inflammation associated with many neurodegenerative diseases.
It was found that the hypoxic episode triggered the release of adenosine, the main component of ATP (your neurons’ fuel). Adenosine is released when a cell is damaged, and this leakage into the environment outside the cell begins a cascade that leads to inflammation (the adenosine activates an enzyme, caspase-1, which triggers production of the cytokine IL-1β).
But caffeine blocks adenosine receptors, stopping the cascade before it starts.
The finding gives support to the idea that caffeine may help prevent cognitive decline and impairment.
(2012). Hypoxia/Reoxygenation Impairs Memory Formation via Adenosine-Dependent Activation of Caspase 1.
The Journal of Neuroscience. 32(40), 13945 - 13955.
Older adults who sleep poorly react to stress with increased inflammation
A study involving 83 older adults (average age 61) has found that poor sleepers reacted to a stressful situation with a significantly greater inflammatory response than good sleepers. High levels of inflammation increase the risk of several disorders, including cardiovascular disease and diabetes, and have been implicated in Alzheimer’s.
Each participant completed a self-report of sleep quality, perceived stress, loneliness and medication use. Around 27% were categorized as poor sleepers. Participants were given a series of tests of verbal and working memory designed to increase stress, with blood being taken before and after testing, as well as three more times over the next hour. The blood was tested for levels of a protein marker for inflammation (interleukin-6).
Poor sleepers reported more depressive symptoms, more loneliness and more perceived stress compared to good sleepers. Before cognitive testing, levels of IL-6 were the same for poor and good sleepers. However, while both groups showed increases in IL-6 after testing, poor sleepers showed a significantly larger increase — as much as four times larger and at a level found to increase risk for illness and death in older adults.
After accounting for loneliness, depression or perceived stress, this association remained. Surprisingly, there was no evidence that poor sleep led to worse cognitive performance, thus causing more stress. Poor sleepers did just as well on the tests as the good sleepers (although I note that we cannot rule out that poor sleepers were having to put in more effort to achieve the same results). Although there was a tendency for poor sleepers to be in a worse mood after testing (perhaps because they had to put in more effort? My own speculation), this mood change didn’t predict the increased inflammatory response.
The findings add to evidence that poor sleep (unfortunately common as people age) is an independent risk factor for cognitive and physical health, and suggest we should put more effort into dealing with it, rather than just accepting it as a corollary of age.
REM sleep disorder doubles risk of MCI, Parkinson's
A recent Mayo Clinic study has also found that people with rapid eye movement sleep behavior disorder (RBD) have twice the risk of developing mild cognitive impairment or Parkinson’s disease. Some 34% of those diagnosed with probable RBD developed MCI or Parkinson's disease within four years of entering the study, a rate 2.2 times greater than those with normal REM sleep.
Earlier research has found that 45% of those with RBD developed MCI or Parkinson's disease within five years of diagnosis, but these findings were based on clinical patients. The present study involved cognitively healthy older adults (70-89) participating in a population-based study of aging, who were diagnosed for probable RBD on the basis of the Mayo Sleep Questionnaire.
(2012). Sleep Disturbance and Older Adultsʼ Inflammatory Responses to Acute Stress.
American Journal of Geriatric Psychiatry. 1 - 1.
(2012). Probable rapid eye movement sleep behavior disorder increases risk for mild cognitive impairment and Parkinson disease: A population‐based study.
Annals of Neurology. 71(1), 49 - 56.
In the first mouse study, when young and old mice were conjoined, allowing blood to flow between the two, the young mice showed a decrease in neurogenesis while the old mice showed an increase. When blood plasma was then taken from old mice and injected into young mice, there was a similar decrease in neurogenesis, and impairments in memory and learning.
Analysis of the concentrations of blood proteins in the conjoined animals revealed the chemokine (a type of cytokine) whose level in the blood showed the biggest change — CCL11, or eotaxin. When this was injected into young mice, they indeed showed a decrease in neurogenesis, and this was reversed once an antibody for the chemokine was injected. Blood levels of CCL11 were found to increase with age in both mice and humans.
The chemokine was a surprise, because to date the only known role of CCL11 is that of attracting immune cells involved in allergy and asthma. It is thought that most likely it doesn’t have a direct effect on neurogenesis, but has its effect through, perhaps, triggering immune cells to produce inflammation.
Exercise is known to at least partially reverse loss of neurogenesis. Exercise has also been shown to produce chemicals that prevent inflammation. Following research showing that exercise after brain injury can help the brain repair itself, another mouse study has found that mice who exercised regularly produced interleukin-6 (a cytokine involved in immune response) in the hippocampus. When the mice were then exposed to a chemical that destroys the hippocampus, the interleukin-6 dampened the harmful inflammatory response, and prevented the loss of function that is usually observed.
One of the actions of interleukin-6 that brings about a reduction in inflammation is to inhibit tumor necrosis factor. Interestingly, I previously reported on a finding that inhibiting tumor necrosis factor in mice decreased cognitive decline that often follows surgery.
This suggests not only that exercise helps protect the brain from the damage caused by inflammation, but also that it might help protect against other damage, such as that caused by environmental toxins, injury, or post-surgical cognitive decline. The curry spice cucurmin, and green tea, are also thought to inhibit tumor necrosis factor.
(2011). The ageing systemic milieu negatively regulates neurogenesis and cognitive function.
Nature. 477(7362), 90 - 94.
(2011). Voluntary exercise protects hippocampal neurons from trimethyltin injury: Possible role of interleukin-6 to modulate tumor necrosis factor receptor-mediated neurotoxicity.
Brain, Behavior, and Immunity. 25(6), 1063 - 1077.
A three-year study following 1,262 healthy older Canadians (aged 67-84) has found that, among those who exercised little, those who had high-salt diets showed significantly greater cognitive decline. On the bright side, sedentary older adults who had low-salt consumption did not show cognitive decline over the three years. And those who had higher levels of physical activity did not show any association between salt and cognition.
Low sodium intake is associated with reduced blood pressure and risk of heart disease, adding even more weight to the mantra: what’s good for the heart is good for the brain.
The analysis controlled for age, sex, education, waist circumference, diabetes, and dietary intakes. Salt intake was based on a food frequency questionnaire. Low sodium intake was defined as not exceeding 2,263 mg/day; mid sodium intake 3,090 mg/day; and high sodium intake 3,091 and greater mg/day. A third of the participants fell into each group. Physical activity was also measured by a self-reported questionnaire (Physical Activity Scale for the Elderly). Cognitive function was measured by the Modified MMSE.
And adding to the evidence that exercise is good for you (not that we really need any more!), a rat study has found that aging rats that ran just over half a kilometer each week were protected against long-term memory loss that can happen suddenly following bacterial infection.
Previous research found that older rats experienced memory loss following E. coli infection, but young adult rats did not. In the older animals, microglia (the brain’s immune cells) were more sensitive to infection, releasing greater quantities of inflammatory molecules called cytokines in the hippocampus. This exaggerated response brought about impairments in synaptic plasticity (the neural changes that underlie learning) and reductions in BDNF.
In this study, the rats were given unlimited access to running wheels. Although the old rats only ran an average of 0.43 miles per week (50 times less distance than the young rats), they performed better on a memory test than rats who only had access to a locked exercise wheel. Moreover, the runners performed as well on the memory test as rats that were not exposed to E. coli.
The researchers are now planning to examine the role that stress hormones may play in sensitizing microglia, and whether physical exercise slows these hormones in older rats.
(Submitted). Sodium intake and physical activity impact cognitive maintenance in older adults: the NuAge Study.
Neurobiology of Aging.
(2011). Little Exercise, Big Effects: Reversing Aging and Infection-Induced Memory Deficits, and Underlying Processes.
The Journal of Neuroscience. 31(32), 11578 - 11586.
Following on from indications that gum disease might be a risk factor for dementia, analysis of data from 152 subjects in the Danish Glostrop Aging Study has revealed that periodontal inflammation at age 70 was strongly associated with lower cognitive scores (on the Digit Symbol Test). Those with periodontal inflammation were nine times more likely to test in the lower range compared to those with little or no periodontal inflammation. A larger follow-up study, among a more ethnically diverse range of subjects, is planned. I hope they also plan to extend the cognitive testing.
The findings were presented by Dr. Angela Kamer at the 2010 annual meeting of the International Association for Dental Research July 16, in Barcelona, Spain.
Older news items (pre-2010) brought over from the old website
Repeated common infections may lead to memory deficits over a lifetime
A mouse study suggests that over the lifetime of an individual, a picornavirus-related infection could have a permanent effect on memory late in life. Picornaviruses are the most common infectious viral agents in humans. They include rhinoviruses, enteroviruses, encephalitis, myocarditis, meningitis, and those that cause foot-and-mouth disease, polio and hepatitis A. Generally individuals contract two or three enterovirus and/or rhinovirus infections each year. In the study, mice infected with an encephalomyelitis virus (comparable to the human poliovirus) had difficulty learning to navigate a maze designed to test various components of spatial memory. The degree of memory impairment was directly correlated to the number of dead brain cells in the hippocampus. "Our findings suggest that picornavirus infections throughout the lifetime of an individual may chip away at the cognitive reserve, increasing the likelihood of detectable cognitive impairment as the individual ages. We hypothesize that mild memory and cognitive impairments of unknown etiology may, in fact, be due to accumulative loss of hippocampus function caused by repeated infection with common and widespread neurovirulent picornaviruses."
Buenz, E.J., Rodriguez, M. & Howe, C.L. 2006. Disrupted spatial memory is a consequence of picornavirus infection. Neurobiology of Disease, 24 (2), 266-273.
Immune function important for cognition
New research overturns previous beliefs that immune cells play no part in — and may indeed constitute a danger to — the brain. Following on from an earlier study that suggested that T cells — immune cells that recognize brain proteins — have the potential to fight off neurodegenerative conditions such as Alzheimer’s, researchers have found that neurogenesis in adult rats kept in stimulating environments requires these immune cells. A further study found that mice with these T cells performed better at some tasks than mice lacking the cells. The researchers suggest that age-related cognitive decline may be related to this, as aging is associated with a decrease in immune system function, suggesting that boosting the immune system may also benefit cognitive function in older adults.
Ziv, Y., Ron, N., Butovsky, O., Landa, G., Sudai, E., Greenberg, N., Cohen, H., Kipnis, J. & Schwartz, M. 2006. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nature Neuroscience, 9, 268 - 275.