mild cognitive impairment
Data from over 11,500 participants in the Atherosclerosis Risk in Communities (ARIC) cohort has found evidence that orthostatic hypotension in middle age may increase the risk of cognitive impairment and dementia 20 years later.
Orthostatic hypotension is the name for the experience of dizziness or light-headedness on standing up. Previous research has suggested an association between orthostatic hypotension and cognitive decline in older adults.
In this study, participants aged 45-64 were tested for orthostatic hypotension in 1987. Those with it (703, around 6%) were 40% more likely to develop dementia in the next 20 years. They also had some 15% more cognitive decline.
Orthostatic hypotension was defined as a drop of 20 mmHg or more in systolic blood pressure or 10 mmHg or more in diastolic blood pressure, when the individual stood up after 20 minutes lying down.
More work is needed to understand the reason for the association.
Rawlings, Andreea. 2017. Orthostatic Hypotension is Associated with 20-year Cognitive Decline and Incident Dementia: The Atherosclerosis Risk in Communities (ARIC) Study. Presented March 10 at the American Heart Association's EPI|LIFESTYLE 2017 Scientific Sessions in Portland, Oregon.
A study involving 35 adults with MCI found that those who exercised four times a week over a six-month period increased their volume of gray matter. But those who participated in aerobic exercise experienced significantly greater gains than those who just stretched, who also showed signs of white matter loss.
Aerobic activity included treadmill, stationary bike or elliptical training.
The study was presented at the annual meeting of the Radiological Society of North America (RSNA) in November, 2016.
In the past few months, several studies have come out showing the value of three different tests of people's sense of smell for improving the accuracy of MCI and Alzheimer's diagnosis, or pointing to increased risk. The studies also add to growing evidence that a decline in sense of smell is an early marker for mild cognitive impairment and Alzheimer’s. Indeed, it appears that this sensory loss is a very early symptom, preceding even the shrinking of the entorhinal cortex (the first brain region to show signs of atrophy).
A simple, commercially available test known as the Sniffin' Sticks Odor Identification Test, in which subjects must try to identify 16 different odors, was given to 728 older adults, as well as a standard cognitive test (the Montreal Cognitive Assessment).
The participants had already been evaluated by doctors and classified as being healthy (292 subjects), having MCI (174: 150 aMCI, 24 naMCI), or having Alzheimer's (262).
It was found that, while the cognitive test alone correctly classified 75% of people with MCI, the number rose to 87% when the sniff test results were added. Diagnosis of Alzheimer's, and of subtypes within MCI, was also improved.
The smell test normally takes 5 to 8 minutes to administer; the researchers are trying to get it down to 3 minutes, to encourage greater use.
Another recent study validates a new smell test which is rather more complicated. The test was developed because the standard University of Pennsylvania Smell Identification Test doesn’t take into account the great variation in olfactory ability among healthy individuals. The ability of normal individuals to recognize and discriminate between odors can vary by as much as 40 times!
The new test is actually four tests:
The study involved 183 older adults, of whom 70 were cognitively normal, 74 tested normal but were concerned about their cognitive abilities, 29 had MCI and 10 had been diagnosed with possible or probable Alzheimer's disease.
Results of the OPID-20 test significantly differentiated among the four groups of participants, and those results correlated with the thinning of the hippocampus and the entorhinal cortex. Participants' ability to remember a previously presented aroma, as reflected in the POEM score, was also significant, with participants with Alzheimer's disease performing at no better than chance.
POEM scores of the two cognitively normal groups were compared with what would have been predicted based on their ability to identify and differentiate between odors, as reflected in the OAS and OD tests. Poor POEM performers were more likely to have the ‘Alzheimer's gene’ (APOEe4), showed thinning of the entorhinal cortex, and poorer cognitive performance over time.
However, two 2016 studies support the use of the University of Pennsylvania Smell Identification Test (UPSIT), and suggest it may offer a practical, low-cost alternative to other tests.
In one study, UPSIT was administered to 397 older adults (average age 80) without dementia, who were also given an MRI scan to measure the thickness of the entorhinal cortex (the first brain region to be affected by Alzheimer's disease). After four years, 50 participants (12.6%) had developed dementia, and nearly 20% had signs of cognitive decline.
Low UPSIT scores, but not entorhinal cortical thickness, were significantly associated with dementia and Alzheimer's disease, and with cognitive impairment. Entorhinal cortical thickness was significantly associated with UPSIT score in those who transitioned from MCI to dementia.
In other words, it looks like impairment in odor identification precedes thinning in the entorhinal cortex.
In another study, UPSITwas administered to 84 older adults, of whom 58 had MCI, as well as either beta amyloid PET scanning or analysis of cerebrospinal fluid. After six months, 67% had signs of memory decline, and this was predicted by amyloid-beta levels (assessed by either method), but not UPSIT score. However, participants with a score of less than 35 were more than three times as likely to have memory decline as those with higher UPSIT scores.
The researchers suggest the association wasn’t as strong in this study because of the younger age of participants (median age 71), their higher education, and the short follow-up.
 Quarmley M, Moberg PJ, Mechanic-Hamilton D, Kabadi S, Arnold SE, Wolk DA, Roalf DR. Odor Identification Screening Improves Diagnostic Classification in Incipient Alzheimer’s Disease. Journal of Alzheimer's Disease [Internet]. 2017 ;55(4):1497 - 1507. Available from: http://content.iospress.com/articles/journal-of-alzheimers-disease/jad160842
 Dhilla AAlefiya, Asafu-Adjei J, Delaney MK, Kelly KE, Gomez-Isla T, Blacker D, Johnson KA, Sperling RA, Hyman BT, Betensky RA, et al. Episodic memory of odors stratifies Alzheimer biomarkers in normal elderly. Annals of Neurology [Internet]. 2016 ;80(6):846 - 857. Available from: http://onlinelibrary.wiley.com/doi/10.1002/ana.24792/abstract
Lee, Seonjoo et al. 2016. Predictive Utility of Entorhinal Cortex Thinning and Odor Identification Test for Transition to Dementia and Cognitive Decline in an Urban Community Population. Presented at the Alzheimer's Association's International Conference in Toronto.
Kreisl, William et al. 2016. Both Odor Identification and Amyloid Status Predict Memory Decline in Older Adults. Presented at the Alzheimer's Association's International Conference in Toronto.
A study comparing the language abilities of 22 healthy young individuals, 24 healthy older individuals and 22 people with MCI, has found that those with MCI:
So, for example, when given an exercise in which they had to join up three words (e.g., “pen”, “ink” and “paper”), the healthy volunteers typically joined the three in a simple sentence, while the MCI group gave circuitous accounts such as going to the shop and buying a pen.
Additionally, when asked to repeat phrases read out by the interviewer, those with MCI had trouble when given phrases involving ambiguous pronouns (e.g., “Fred visited Bob after his graduation”), although they had no trouble with more complex sentences.
A caveat: if you're just one of those people who has always talked like this, don't panic! It's a matter of change and deterioration, not a stable personality trait.
Janet Sherman presented the findings at the annual meeting of the American Association for the Advancement of Science in Boston, in February 2017.
Following on from a previous study showing that such a virtual supermarket game administered by a trained professional can detect MCI, a small study used a modified Virtual SuperMarket Remote Assessment Routine (VSM-RAR) that was self-administered by the patient at home on their own, for a period of one month.
Using the average score over 20 assessments, the game correctly diagnosed MCI 91.8% of the time, a level of diagnostic accuracy similar to the most accurate standardized neuropsychological tests.
The study involved six patients with MCI and six healthy older adults.The level of diagnostic accuracy was better using the average score than in the previous study in which only a single score was used.
A tablet PC was provided to the participants, on which to play the game.
 Zygouris S, Ntovas K, Giakoumis D, Votis K, Doumpoulakis S, Segkouli S, Karagiannidis C, Tzovaras D, Tsolaki M. A Preliminary Study on the Feasibility of Using a Virtual Reality Cognitive Training Application for Remote Detection of Mild Cognitive Impairment. Journal of Alzheimer's Disease [Internet]. 2017 ;56(2):619 - 627. Available from: http://content.iospress.com/articles/journal-of-alzheimers-disease/jad160518
Data from the Women's Health Initiative Memory Study, involving 6,467 postmenopausal women (65+) who reported some level of caffeine consumption, has found that those who consumed above average amounts of coffee had a lower risk of developing dementia.
Caffeine intake was estimated from a questionnaire. The median intake was 172 mg per day (an 8-ounce cup of brewed coffee contains 95mg of caffeine, 8-ounces of brewed black tea contains 47mg, so slightly less than 2 cups of coffee or less than 4 cups of tea). The women were cognitively assessed annually.
Over ten years, 388 were diagnosed with probable dementia (209) or MCI (179). Those who consumed above the median amount of caffeine had a 36% reduction in risk. The average intake in this group was 261 mg (3 cups of coffee), while the average intake for those below the median was 64 mg per day (less than one cup).
Risk factors such as hormone therapy, age, race, education, body mass index, sleep quality, depression, hypertension, prior cardiovascular disease, diabetes, smoking, and alcohol consumption, were taken into account.
The findings are consistent with other research finding a benefit for older women. It should not be assumed that the findings apply to men. It also appears that there may be a difference depending on education level. This sample had a high proportion of college-educated women.
It should also be noted that there was no clear dose-response effect — we could put more weight on the results if there was a clear relationship between amount of caffeine and benefit. Part of the problem here, however, is that it’s difficult to accurately assess the amount of caffeine, given that it’s based on self-report intake of coffee and tea, and the amount of caffeine in different beverages varies significantly.
Moreover, we do have a couple of mechanisms for caffeine to help fight age-related cognitive decline.
A recent study using rats modified to have impaired receptors for the adenosine A2A produced rats showing typical characteristics of an aging brain. In humans, too, age-related cognitive decline has been associated with over-activation of these receptors and dysfunction in glucocorticoid receptors.
The rat study shows that over-activation of the adenosine A2A receptors reduces the levels of glucocorticoid receptors in the hippocampus, which in turn impairs synaptic plasticity and cognition. In other words, it is the over-activation of the adenosine receptors that triggers a process that ends with cognitive impairment.
The point of all this is that caffeine inhibits the adenosine A2A receptors, and when the rats were given a caffeine analogue, their memory deficits returned to normal.
Another more recent study has found that caffeine increases the production of an enzyme that helps prevent tau tangles.
Building on previous research finding that an enzyme called NMNAT2 not only protects neurons from stress, but also helps prevent misfolded tau proteins (linked to Alzheimer’s, and other neurodegenerative disorders), the study identified 24 compounds (out of 1,280 tested) as having potential to increase the production of NMNAT2. One of the most effective of these was caffeine.
When caffeine was given to mice modified to produce lower levels of NMNAT2, the mice began to produce the same levels of the enzyme as normal mice.
 Driscoll I, Shumaker SA, Snively BM, Margolis KL, Manson JAE, Vitolins MZ, Rossom RC, Espeland MA. Relationships Between Caffeine Intake and Risk for Probable Dementia or Global Cognitive Impairment: The Women’s Health Initiative Memory Study. The Journals of Gerontology: Series A [Internet]. 2016 ;71(12):1596 - 1602. Available from: https://academic.oup.com/biomedgerontology/article/71/12/1596/2513764/Relationships-Between-Caffeine-Intake-and-Risk-for
 Batalha VL, Ferreira DG, Coelho JE, Valadas JS, Gomes R, Temido-Ferreira M, Shmidt T, Baqi Y, Buée L, Müller CE, et al. The caffeine-binding adenosine A2A receptor induces age-like HPA-axis dysfunction by targeting glucocorticoid receptor function. Scientific Reports [Internet]. 2016 ;6:31493. Available from: http://www.nature.com/srep/2016/160811/srep31493/full/srep31493.html
 Ali YO, Bradley G, Lu H-C. Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons. Scientific Reports [Internet]. 2017 ;7:43846. Available from: http://www.nature.com/srep/2017/170307/srep43846/full/srep43846.html
Data from 876 patients (average age 78) in the 30-year Cardiovascular Health Study show that virtually any type of aerobic physical activity can improve brain volume and reduce Alzheimer's risk.
A higher level of physical activity was associated with larger brain volumes in the frontal, temporal, and parietal lobes including the hippocampus, thalamus and basal ganglia. Among those with MCI or Alzheimer's (25% of the participants), higher levels of physical activity were also associated with less brain atrophy. An increase in physical activity was also associated with larger grey matter volumes in the left inferior orbitofrontal cortex and the left precuneus.
Further analysis of 326 of the participants found that those with the highest energy expenditure were half as likely to have developed Alzheimer's disease five years later.
Physical activity was assessed using the Minnesota Leisure-Time Activities questionnaire, which calculates kilocalories/week using frequency and duration of time spent in 15 different leisure-time activities: swimming, hiking, aerobics, jogging, tennis, racquetball, walking, gardening, mowing, raking, golfing, bicycling, dancing, calisthenics, and riding an exercise cycle.
The study does not look at whether some types of physical activity are better than others, unfortunately, but its message that overall physical activity, regardless of type, helps in the fight against cognitive impairment is encouraging.
 Raji CA, Merrill DA, Eyre H, Mallam S, Torosyan N, Erickson KI, Lopez OL, Becker JT, Carmichael OT, H. Gach M, et al. Longitudinal Relationships between Caloric Expenditure and Gray Matter in the Cardiovascular Health Study. Journal of Alzheimer's disease: JAD. 2016 .
A large study has found that mild cognitive impairment occurred twice as often in older adults diagnosed with type 2 diabetes.
A German study involving 1,936 older adults (50+) has found that mild cognitive impairment (MCI) occurred twice as often in those diagnosed with type 2 diabetes.
Analysis of 560 participants with MCI (289 with amnestic MCI and 271 with non-amnestic MCI) and 1,376 cognitively normal participants revealed that this was only observed in middle-aged participants (50-65), not in older participants (65-80). Interestingly, there was a gender difference. Middle-aged women showed a stronger association between diabetes and amnestic MCI, while middle-aged men showed a stronger association with non-amnestic MCI.
Winkler, A., Dlugaj, M., Weimar, C., Jöckel, K.-H., Erbel, R., Dragano, N., & Moebus, S. (2014). Association of diabetes mellitus and mild cognitive impairment in middle-aged men and women. Journal of Alzheimer’s Disease: JAD, 42(4), 1269–1277. http://doi.org/10.3233/JAD-140696
A study involving 266 people with mild cognitive impairment (aged 70+) has found that B vitamins are more effective in slowing cognitive decline when people have higher omega 3 levels.
Participants were randomly selected to receive either a B-vitamin supplement (folic acid, vitamins B6 and B12) or a placebo pill for two years. The vitamins had little to no effect for those with low levels of omega-3 fatty acids, but were very effective for those with high baseline omega-3 levels.
Levels of DHA appeared to be more important than levels of EPA, but more research is needed to confirm that.
The finding may help to explain why research looking at the effects of B vitamins, or the effects of omega-3 oils, have produced inconsistent findings.
The study followed research showing that B vitamins can slow or prevent brain atrophy and memory decline in people with MCI, and they were most effective in those who had above average blood levels of homocysteine.
 Oulhaj A, Jernerén F, Refsum H, A. Smith D, de Jager CA. Omega-3 Fatty Acid Status Enhances the Prevention of Cognitive Decline by B Vitamins in Mild Cognitive Impairment. Journal of Alzheimer's Disease [Internet]. 2016 ;50(2):547 - 557. Available from: http://www.medra.org/servlet/aliasResolver?alias=iospress&doi=10.3233/JAD-150777
A large, two-year study challenges the evidence that regular exercise helps prevent age-related cognitive decline.
The study involved 1,635 older adults (70-89) who were enrolled in the Lifestyle Interventions and Independence for Elders (LIFE) study. They were sedentary adults who were at risk for mobility disability but able to walk about a quarter mile. Participants had no significant cognitive impairment (as measured by the MMSE) at the beginning of the study. Around 90% (1476) made it to the end of the study, and were included in the analysis.
Half the participants were randomly assigned to a structured, moderate-intensity physical activity program that included walking, resistance training, and flexibility exercises, and the other half to a health education program of educational workshops and upper-extremity stretching.
In the physical activity condition, participants were expected to attend 2 center-based visits per week and perform home-based activity 3 to 4 times per week. The sessions progressed toward a goal of 30 minutes of walking at moderate intensity, 10 minutes of primarily lower-extremity strength training with ankle weights, and 10 minutes of balance training and large muscle group flexibility exercises.
The health education group attended weekly health education workshops during the first 26 weeks of the intervention and at least monthly sessions thereafter. Sessions lasted 60 to 90 minutes and consisted of interactive and didactic presentations, facilitator demonstrations, guest speakers, or field trips. Sessions included approximately 10 minutes of group discussion and interaction and 5 to 10 minutes of upper-extremity stretching and flexibility exercises.
Cognitive assessments were made at the beginning of the study and at 24 months, as well as a computerized assessment at either 18 or 30 months.
At the end of the study, there was no significant difference in cognitive score, or incidence of MCI or dementia, between the two groups. However, those in the exercise group who were 80 years or older ( 307) and those with poorer baseline physical performance ( 328) did show significantly better performance in executive function.
Executive function is not only a critical function in retaining the ability to live independently, research has also shown that it is the most sensitive cognitive domain to physical exercise.
Note also that there was no absolute control group — that is, people who received no intervention. Both groups showed remarkably stable cognitive scores over the two years, suggesting that both interventions were in fact effective in “holding the line”.
While this finding is disappointing and a little surprising, it is not entirely inconsistent with the research. Studies into the benefits of physical exercise for fighting age-related cognitive decline and dementia have produced mixed results. It does seem clear that the relationship is not a simple one, and what's needed is a better understanding of the complexities of the relationship. For example, elements of exercise that are critical, and the types of people (genes; health; previous social, physical, and cognitive attributes) that may benefit.
 Sink KM, Espeland MA, Castro CM, et al. Effect of a 24-month physical activity intervention vs health education on cognitive outcomes in sedentary older adults: The life randomized trial. JAMA [Internet]. 2015 ;314(8):781 - 790. Available from: http://dx.doi.org/10.1001/jama.2015.9617
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