mild cognitive impairment
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
A large meta-analysis has concluded that having diabetes increases the chance that a person with mild cognitive impairment will progress to dementia by 65%.
There was no consistent evidence that hypertension or cholesterol levels increased the risk of someone with MCI progressing to dementia. Smoking was similarly not associated with increased risk, although the reason for this probably lies in mortality: smokers tend to die before developing dementia.
There was some evidence that having symptoms of psychiatric conditions, including depression, increased the risk of progressing to dementia.
There was some evidence that following a Mediterranean diet decreased the risk of an individual with amnestic MCI progressing to Alzheimer's, and that higher folate levels decrease the risk of progressing from MCI to dementia. The evidence regarding homocysteine levels was inconsistent.
The evidence indicates that level of education does not affect the risk of someone with MCI progressing to dementia.
Do note that all this is solely about progression from MCI to dementia, not about overall risk of developing dementia. Risk factors are complex. For example, cholesterol levels in mid-life are associated with the later development of dementia, but cholesterol levels later in life are not. This is consistent with cholesterol levels not predicting progression from MCI to dementia. Level of education is a known risk factor for dementia, but it acts by masking the damage in the brain, not preventing it. It is not surprising, therefore, that it doesn't affect progression from MCI to dementia, because higher education helps delay the start, it doesn't slow the rate of decline.
Do note also that a meta-analysis is only as good as the studies it's reviewing! Some factors couldn't be investigated because they haven't been sufficiently studied in this particular population (those with MCI).
The long-running Cache County study has previously found that 46% of those with MCI progressed to dementia within three years; this compared with 3% of those (age-matched) with no cognitive impairment at the beginning of the study.
More recently, data from the long-running, population-based Rotterdam study revealed that those diagnosed with MCI were four times more likely to develop dementia, over seven years. compared with those without MCI. Of those with MCI (10% of the 4,198 study participants), 40% had amnestic MCI — the form of MCI that is more closely associated with Alzheimer's disease.
The 2014 study also found that older age, positive APOE-ɛ4 status, low total cholesterol levels, and stroke, were all risk factors for MCI. Having the APOE-ɛ4 genotype and smoking were related only to amnestic MCI. Waist circumference, hypertension, and diabetes were not significantly associated with MCI. This may be related to medical treatment — research has suggested that hypertension and diabetes may be significant risk factors only when untreated or managed poorly.
 Cooper C, Sommerlad A, Lyketsos CG, Livingston G. Modifiable Predictors of Dementia in Mild Cognitive Impairment: A Systematic Review and Meta-Analysis. American Journal of Psychiatry [Internet]. 2015 ;172(4):323 - 334. Available from: http://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2014.14070878
 Tschanz JT, Welsh-Bohmer KA, Lyketsos CG, Corcoran C, Green RC, Hayden K, Norton MC, Zandi PP, Toone L, West NA, et al. Conversion to dementia from mild cognitive disorder The Cache County Study. Neurology [Internet]. 2006 ;67(2):229 - 234. Available from: http://www.neurology.org/content/67/2/229
de Bruijn, R.F.A.G. et al. Determinants, MRI Correlates, and Prognosis of Mild Cognitive Impairment: The Rotterdam Study. Journal of Alzheimer’s Disease, Volume 42/Supplement 3 (August 2014): 2013 International Congress on Vascular Dementia (Guest Editor: Amos D. Korczyn), DOI: 10.3233/JAD-132558.
Read the article at Mempowered
A three-year study involving 169 people with MCI has found that those who later developed Alzheimer's disease showed 10-30% greater atrophy in two specific locations within the hippocampus, the cornu ammonis (CA1) and the subiculum. A second study comparing the brains of 10 cognitively normal elderly people and seven who were diagnosed with MCI between two and three years after their initial brain scan and with Alzheimer's some seven years after the initial scan, has confirmed the same pattern of hippocampal atrophy, from the CA1 to the subiculum, and then other regions of the hippocampus.
Apostolova, L. G., Thompson, P. M., Green, A. E., Hwang, K. S., Zoumalan, C., Jr, C. R. J., Harvey, D. J., et al. (2010). 3D comparison of low, intermediate, and advanced hippocampal atrophy in MCI. Human Brain Mapping, 9999(9999), NA. doi:10.1002/hbm.20905
Apostolova, L.G. et al. In press. Subregional hippocampal atrophy predicts Alzheimer's dementia in the cognitively normal. Neurobiology of Aging, Available online 24 September 2008.
A study involving 117 healthy elderly (aged 60-91) has found that, while increasing age was associated with poorer memory for names of famous people, age didn’t affect memory for biographical details about them. It also found that names served as better cues to those details than faces did. A follow-up study (to be published in Neuropsychologia) found that, in contrast, those with mild cognitive impairment and early Alzheimer’s showed not only an increased inability to remember names, but also a decline in memory for biographical details.
Langlois, R. et al. 2009. Manque du nom propre et effet de la modalité sur la capacité à reconnaître des personnes connues au cours du vieillissement normal. Canadian Journal on Aging/ La Revue canadienne du vieillissement, 28 (4), 337-345.
A study involving 176 patients with Alzheimer's, vascular dementia or mixed dementia, or mild cognitive impairment, has found that 82% of the patients with changes in their white matter were apathetic, compared to an overall rate of 58%. This discovery suggests that there is a common biological reason behind this apathy, irrespective of which type of dementia a patient has. White matter changes were also associated with age, gender, blood pressure, hypertension, ischaemic heart disease, mental slowness, disinhibition, gait disturbance and focal neurologic symptoms. Apathy, mental slowness and age were the most consistent predicting factors for WMCs.
Jonsson, M., Edman, Å., Lind, K., Rolstad, S., Sjögren, M., & Wallin, A. (2009). Apathy is a prominent neuropsychiatric feature of radiological white-matter changes in patients with dementia. International Journal of Geriatric Psychiatry, 9999(9999), n/a. doi: 10.1002/gps.2379.
A study involving 111 older adults with mild cognitive impairment, of whom 28 progressed from mild cognitive impairment to dementia over the next 2 ½ years, found only one factor predicted conversion from mild cognitive impairment to dementia: the degree of functional impairment (ability to perform routine activities) at the beginning of the study. Other cognitive and neurological variables were not predictive.
Farias, S.T. et al. 2009. Progression of Mild Cognitive Impairment to Dementia in Clinic- vs Community-Based Cohorts. Archives of Neurology, 66(9), 1151-1157.
A study involving 76 older people with no memory problems and 87 older people with amnestic mild cognitive impairment has found that those (25 of the 87) who had developed Alzheimer’s a year later were significantly worse at a money management task. Compared to those with no memory problems, as well as those with MCI who did not develop dementia, those who did develop Alzheimer’s not only dropped 9% on checkbook management abilities and 6% on overall financial knowledge and skills, but also performed more poorly at the beginning of the study. The task included counting coins, making grocery purchases, understanding and using a checkbook, understanding and using a bank statement, preparing bills for mailing, and detecting fraud situations.
Triebel, K.L. et al. 2009. Declining financial capacity in mild cognitive impairment: A 1-year longitudinal study. Neurology, 73, 928-934.
A study involving 679 seniors (65+) has found that those with small areas of brain damage called white matter hyperintensities, often referred to as ministrokes, were nearly twice as likely to have mild cognitive impairment that included memory loss (amnestic MCI), while those who had infarcts (areas of dead tissue usually called strokes) were more likely to experience mild cognitive impairment in abilities other than memory loss (non-amnestic MCI). In other words, ministrokes predicted memory problems, while strokes predicted non-memory problems.
Luchsinger, J.A. et al. 2009. Subclinical cerebrovascular disease in mild cognitive impairment. Neurology, 73, 450-456.
In a study in which 49 seniors (65+) were followed for an average of 9.5 years, of whom 24 developed mild cognitive impairment, those with the fastest rate of growth in white matter lesions were more likely to develop mild cognitive impairment than those with a slow rate of growth. The amount of lesions in healthy brains at the start of the study was not a factor; the crucial factor was the rate of progression.
Silbert, L.C. et al. 2009. Cognitive impairment risk: White matter hyperintensity progression matters. Neurology, 73, 120-125.
A study involving 269 patients with mild cognitive impairment provides evidence that a fully automated procedure called Volumetric MRI (that can be done in a clinical setting) can accurately and quickly measure parts of the medial temporal lobe and compare them to expected size. It also found that not only atrophy in the hippocampus but also the amygdala is associated with a greater risk of conversion to Alzheimer’s.
Kovacevic, S. et al. 2009. High-throughput, Fully Automated Volumetry for Prediction of MMSE and CDR Decline in Mild Cognitive Impairment. Alzheimer Disease & Associated Disorders, 23 (2), 139-145.
A study involving 60 patients with subjective cognitive impairment, 37 patients with non-amnestic mild cognitive impairment, and 71 with amnestic mild cognitive impairment, has found that 52% of those with SCI, 68% of those with naMCI, and 79% of those with aMCI showed decreased concentrations of Aβ42 and increased concentrations of tau protein in the cerebrospinal fluid. The findings confirm the use of biomarkers in the CSF for very early diagnosis.
Visser, P.J. et al. 2009. Prevalence and prognostic value of CSF markers of Alzheimer's disease pathology in patients with subjective cognitive impairment and mild cognitive impairment in the DESCRIPA study: a prospective, case-control study. The Lancet Neurology, 8 (7), 619–627.
A new cognitive test for detecting Alzheimer's has been developed, and designed to be suitable for non-specialist use. The TYM ("test your memory") involves 10 tasks including ability to copy a sentence, semantic knowledge, calculation, verbal fluency and recall ability. It has been tested on 540 healthy individuals and139 patients with diagnosed Alzheimer's or mild cognitive impairment. Healthy controls completed the test in an average time of five minutes and gained an average score of 47 out of 50, compared to 45 for those with mild cognitive impairment, 39 for those with non-Alzheimer dementias and 33 for those with Alzheimer’s. Among controls, the average score was not affected by age until after 70, when it showed a small decline. There were no gender or geographical background differences in performance. The TYM detected 93% of patients with Alzheimer's, compared to only 52% by the widely used mini-mental state examination.
Brown, J. et al. 2009. Self administered cognitive screening test (TYM) for detection of Alzheimer’s disease: cross sectional study. BMJ, 338:b2030, doi: 10.1136/bmj.b2030 Full text available here.
A test first developed for use with nonhuman primates is now being used to detect mild cognitive impairment (MCI) in humans. The infrared eye-tracking test involves showing one image and then another after a 2-second delay, and then repeating the test 2 minutes later. Those without cognitive impairment spend most of their time looking at the new image, but it was found that those with MCI spent less time looking at the new picture, presumably because they have less memory of seeing the original image before. Those with Alzheimer's disease look at both images equally. It’s hoped that this test may allow dementia to be spotted much earlier.
Crutcher, M.D. et al. 2009. Eye Tracking During a Visual Paired Comparison Task as a Predictor of Early Dementia. American Journal of Alzheimer's Disease and Other Dementias, Published online February 26 2009.
Cerebrospinal fluid samples from 410 volunteers (100 with mild Alzheimer’s; 196 with MCI; 114 cognitively normal older adults) has revealed that concentrations of amyloid beta-42 peptide and tau protein successfully assessed brain status and predicted development. The test diagnosed Alzheimer’s with 96% accuracy; ruled out Alzheimer’s with 95% accuracy; and predicted the conversion from MCI to Alzheimer’s with 82% accuracy.
Shaw, L.M. et al. 2009. Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects. Annals of Neurology, Published Online March 18 2009.
Data from 41 studies has revealed the risk of those with mild cognitive impairment developing dementia is much less than thought. MCI is found in about 1 in 6 people seen in general practice, and it was thought that the risk of developing dementia was up to 15% per year, making deterioration almost inevitable within 5 to 10 years. It now appears that the risk is 10% per year in high risk groups (9.6% for dementia overall; 8% for Alzheimers; 2% for vascular dementia) and only 5% per year in low risk groups (5% for dementia overall; 7% for Alzheimers; 1.6% for vascular dementia). More importantly, only 20-40% developed dementia even after 10 years and the risk appeared to reduce slightly with time.
Mitchell, A.J. & Shiri-Feshki, M. 2009. Rate of progression of mild cognitive impairment to dementia – meta-analysis of 41 robust inception cohort studies. Acta Psychiatrica Scandinavica, 119 (4), 252-265.
A study of 84 patients with mild Alzheimer's, 175 patients with MCI and 139 healthy controls has revealed a pattern of regional brain atrophy in patients with MCI that indicates a greater likelihood of progression to Alzheimer's. Brain scans results showed widespread cortical atrophy in some patients with MCI, most importantly, atrophy in parts of the medial and lateral temporal lobes and in the frontal lobes — a pattern also present in the patients with mild Alzheimer's disease. Those exhibiting such atrophy declined significantly over a year and were more likely to progress to a probable diagnosis of Alzheimer's. MCI patients without that pattern of atrophy remained stable after a year. It should be noted that such atrophy affects not only memory, but also planning, organization, problem solving and language.
McEvoy, L.K. et al. 2009. Alzheimer Disease: Quantitative Structural Neuroimaging for Detection and Prediction of Clinical and Structural Changes in Mild Cognitive Impairment. Radiology, Published online February 6.
A new chemical marker called FDDNP, which binds to plaque and tangle deposits in the brain, has enabled PET scans to reveal exactly where these abnormal protein deposits are accumulating, and has found that older age correlated with higher concentrations of FDDNP in the medial and lateral temporal regions of the brain, areas involved with memory, where plaques and tangles usually collect. Of the 76 study volunteers, 34 carried the ‘Alzheimer’s gene’. This group demonstrated higher FDDNP levels in the frontal region of the brain than those without the gene variant. Thirty-six of the volunteers had mild cognitive impairment, and these had higher measures of FDDNP in the medial temporal brain regions than normal volunteers. Those who had both MCI and the APOE-4 gene also had higher concentrations of FDDNP in the medial temporal brain regions than those who had MCI but not APOE-4. The pilot study offers hope of early diagnosis of brain impairment, before symptoms show themselves.
Small, G.W. et al. 2009. Influence of Cognitive Status, Age, and APOE-4 Genetic Risk on Brain FDDNP Positron-Emission Tomography Imaging in Persons Without Dementia. Archives of General Psychiatry, 66(1), 81-87.
A study of 503 seniors (aged 50-85) with no dementia found that 453 of them (90%) reported having occasional memory problems such as having trouble thinking of the right word or forgetting things that happened in the last day or two, or thinking problems such as having trouble concentrating or thinking more slowly than they used to. Such problems have been attributed to white matter lesions, which are very common in older adults, but all of the participants in the study had white matter lesions in their brains, and the amount of lesions was not tied to occasional memory problems. However it was found that those who reported having such problems had a smaller hippocampus than those who had no cognitive problems. This was most noteworthy in subjects with good objective cognitive performance.
van Norden, A.G.W. et al. 2008. Subjective cognitive failures and hippocampal volume in elderly with white matter lesions. Neurology, 71, 1152-1159.
An Australian study involving 138 older adults (50 years and over) with mild cognitive impairment, has found that those who undertook to achieve 2 ½ hours of physical activity each week (three 50 minute sessions), ranging from walking, ballroom dancing to swimming, for a six month period, continually out-scored the control group on cognitive tests during the 18 month testing period — showing that memory improvement was still evident a year after the supervised exercise period.
Lautenschlager, N.T. et al. 2008. Effect of Physical Activity on Cognitive Function in Older Adults at Risk for Alzheimer Disease: A Randomized Trial. Journal of the American Medical Association, 300(9), 1027-1037.
A new, carefully validated questionnaire called Everyday Cognition (ECog) has been developed by seven psychologists. The 39-question screening tool is designed to enable mild functional problems in older adults to be quickly and easily identified. The questionnaire needs to be filled out by someone who knows an older adult well, such as a spouse, adult child, or close friend. It looks at everyday function in seven key cognitive domains: memory, language, semantic (factual) knowledge, visuospatial abilities, planning, organization and divided attention. The test has been shown to be sensitive to early changes present in Mild Cognitive Impairment, and unlike other cognitive tests, does not appear to be strongly influenced by education level. The test even differentiated between people diagnosed with mild impairment in memory only and those mildly impaired in several areas.
Farias, S.T. et al. 2008. The Measurement of Everyday Cognition (ECog): Scale Development and Psychometric Properties. Neuropsychology, 22 ( 4), 531-544.
A study involving over 2000 people between 70 and 89 years old, found 15% had mild cognitive impairment, and men were one-and-a-half times more likely to have MCI than women.
The research was presented at the American Academy of Neurology Annual Meeting in Chicago, April 12–19.
A study of nearly 1000 older adults (average age 76.3) without mild cognitive impairment at the start of the study found that over the follow-up period (average: 4.7 years), 334 individuals developed mild cognitive impairment, of which 160 were amnestic (reduced memory) and 174 were non-amnestic. Hypertension (high blood pressure) was associated with an increased risk of non-amnestic mild cognitive impairment; but not with amnestic mild cognitive impairment.
Reitz, C. et al. 2007. Hypertension and the Risk of Mild Cognitive Impairment. Archives of Neurology, 64(12), 1734-1740.
Older adults who have difficulty identifying common odors may have a greater risk of developing mild cognitive impairment, increasingly recognized as a precursor to Alzheimer’s disease. A study of nearly 600 older adults (average age 79.9) found that 30.1% developed mild cognitive impairment over the five-year period of the study. Risk of developing mild cognitive impairment was greater for those who scored worse on an odor identification test given at the start of the study. For example, those who scored below average (eight) were 50% more likely to develop MCI than those who scored above average (11). This association did not change when stroke, smoking habits or other factors that might influence smell or cognitive ability were considered. Impaired odor identification was also associated with lower cognitive scores at the beginning of the study and with a more rapid decline in episodic memory (memory of past experiences), semantic memory (memory of words and symbols) and perceptual speed. The odor test involved identifying 12 familiar odors given four possible alternatives to choose from.
Wilson, R.S., Schneider, J.A., Arnold, S.E., Tang, Y., Boyle, P.A. & Bennett, D.A. 2007. Olfactory Identification and Incidence of Mild Cognitive Impairment in Older Age. Archives of General Psychiatry, 64, 802-808.
A study involving 120 people over 60 found those who complained of significant memory problems who still performed normally on memory tests had a 3% reduction in gray matter density in their brains. This compares to 4% in those diagnosed with mild cognitive impairment. This suggests that significant memory loss complaints may indicate a very early "pre-MCI" stage of dementia for some people.
Saykin, A.J. et al. 2006. Older adults with cognitive complaints show brain atrophy similar to that of amnestic MCI. Neurology, 67, 834-842.
A study of 20 older adults with mild cognitive impairment has found that the hippocampus was smaller in those who developed into Alzheimer's during the 3 year period.
Apostolova, L.G. et al. 2006. Conversion of Mild Cognitive Impairment to Alzheimer Disease Predicted by Hippocampal Atrophy Maps. Archives of Neurology, 63, 693-699.
Autopsies have revealed that the brains of patients with mild cognitive impairment display pathologic features that appear to place them at an intermediate stage between normal aging and Alzheimer's disease. For instance, the patients had begun developing neurofibrillary tangles, but the number of plaques was similar to that in healthy patients. All patients with mild cognitive impairment had abnormalities in their temporal lobes, which likely caused their cognitive difficulties, and many also had abnormalities in other areas that did not relate to the features of Alzheimer's disease. In a second study, of 34 patients with mild cognitive impairment who had progressed to clinical dementia before their deaths, 24 were diagnosed (post-mortem) with Alzheimer’s, and 10 with other types of dementia. As in the other study, all patients had abnormalities in their temporal lobes.
Petersen, R.C. et al. 2006. Neuropathologic Features of Amnestic Mild Cognitive Impairment. Archives of Neurology, 63, 665-672.
Jicha, G.A. et al. 2006. Neuropathologic Outcome of Mild Cognitive Impairment Following Progression to Clinical Dementia. Archives of Neurology, 63, 674-681.
A study of 3,957 people from the general population of Olmsted County, Minnesota is currently in train to find how many of those who did not have dementia might have mild cognitive impairment. A report on the findings so far suggests 9% of those aged 70 to 79 and nearly 18% of those 80 to 89 have MCI. Prevalence varied not only with age but also years of education: 25% in those with up to eight years of education, 14% in those with nine to 12 years, 9% in those with 13 to 16 years, and 8.5% in those with greater than 16 years.
Findings from this study were presented April 4 at the American Academy of Neurology meeting in San Diego.
Mild cognitive impairment (MCI), a transitional stage between normal cognition and Alzheimer's disease, has been categorized into two sub-types on the basis of differing symptoms. Those with the amnesic subtype (MCI-A) have memory impairments only, while those with the multiple cognitive domain subtype (MCI-MCD) have other types of mild impairments, such as in judgment or language, and mild or no memory loss. Both sub-types progress to Alzheimer's disease at the same rate. A new imaging technique has now revealed that these types do in fact have different pathologies. The hippocampus of patients with MCI-A was not significantly different from that of Alzheimer's patients (who show substantial shrinkage), but the hippocampus of those with MCI-MCD was not significantly different from that of the healthy controls.
Becker, J.T. et al. 2006. Three-dimensional Patterns of Hippocampal Atrophy in Mild Cognitive Impairment. Archives of Neurology, 63, 97-101.
A study involving retired National Football League players found that they had a 37% higher risk of Alzheimer's than other U.S. males of the same age. Some 60.8% of the retired players reported having sustained at least one concussion during their professional playing career, and 24% reported sustaining three or more concussions. Those with three or more concussions had a five-fold greater chance of having been diagnosed with mild cognitive impairment and a three-fold prevalence of reported significant memory problems compared to those players without a history of concussion. As the study was based on self-reported answers to the health questions, further studies are needed to confirm the findings, but it does seem likely that head injuries earlier in life increase the chance of developing dementia or mild cognitive impairment.
Guskiewicz, K.M., Marshall, S.W., Bailes, J., McCrea, M., Cantu, R.C., Randolph, C. & Jordan, B.D. 2005. Association between Recurrent Concussion and Late-Life Cognitive Impairment in Retired Professional Football Players. Neurosurgery, 57(4), 719-726.
Researchers have developed a brain scan-based computer program that quickly and accurately measures metabolic activity in the hippocampus, a key brain region that shrinks with the development of Alzheimer’s. The study followed 53 normal subjects aged 54 to 80 for at least 9 years and in some cases for as long as 24 years, and found that hippocampal glucose metabolism was significantly reduced on the first scan of those 25 individuals who would later experience cognitive decline related to either mild cognitive impairment or to Alzheimer's. The findings bring hope of being able to predict who will develop Alzheimer’s at least 9 years ahead of symptoms.
Mosconi, L., Tsui, W-H., De Santi, S., Li, J., Rusinek, H., Convit, A., Li, Y., Boppana, M. & de Leon, M.J. 2005. Reduced hippocampal metabolism in MCI and AD: Automated FDG-PET image analysis. Neurology, 64, 1860-1867.
A new study has found that rates of total brain volume loss may help identify patients with mild cognitive impairment who are at high risk of developing dementia. The study followed 55 people over 14 years, and found that loss of volume in the hippocampus predicted which mildly cognitively impaired individuals would stay stable and which would decline to Alzheimer's with 70% accuracy, while the rate of total brain volume loss was 62% accurate in predicting cognitive outcome. Combining both variables produced the strongest model: 75% accuracy. The discovery could help doctors plan early treatment strategies and prevention studies.
The study was presented at the 56th annual meeting of the American Academy of Neurology in San Francisco.
Early diagnosis of Alzheimer's is becoming more important with new medical and psychological interventions that can slow (but not stop) the course of the disease. Given this, it is suggested that more sensitive testing may be necessary for highly intelligent people, who, on average, show clinical signs of Alzheimer's later than the general population. Once they show such signs, they decline much faster. A study of 42 older people with IQ's of 120 or more, used two different test norms to forecast problems: the standard norm, derived from a large cross-section of the population, or an adjusted high-IQ norm that measured changes against the individual's higher ability level. The raised cutoffs predicted that 11 of the 42 individuals were at risk for future decline – compared with standard cutoffs, which indicated they were normal. True to the former prediction, three and a half years later, nine of those 11 people had declined. Six of those went on to develop mild cognitive impairment (MCI), a transitional illness from normal aging to a dementia (of which one type is Alzheimer's). Five of these individuals have since received a diagnosis of Alzheimer's disease, two years after this study was submitted. It is also suggested that, at the other end of the scale, those with below-average intelligence have the potential for being misdiagnosed as 'demented' when they are not, and the norms should be adjusted downwards accordingly.
Rentz, D.M., Huh, T.J., Faust, R.R., Budson, A.E., Scinto, L.F.M., Sperling, R.A. & Daffner, K.R. 2004. Use of IQ-Adjusted Norms to Predict Progressive Cognitive Decline in Highly Intelligent Older Individuals. Neuropsychology, 18 (1).
Researchers have developed a brief telephonic questionnaire that helps distinguish between persons with early signs of dementia and persons with normal cognitive function. The questionnaire provides a way to reach out to persons with dementia whose impairment otherwise may go undetected until substantial cognitive deterioration has occurred. The questionnaire consists of a test of delayed recall and 2 questions that ask whether the person needs help with remembering to take medications or with planning a trip for errands. It is estimated that of 100 people who score positive on this test, 42 will actually have cognitive impairment. In other words, this does not provide a diagnosis of Alzheimer’s, but provides evidence that further evaluation is required. The rate of false positives compares favorably to other types of screening tests. A further study is underway to confirm the validity and reliability of the test.
Fillit, H. et al. 2003. A Brief Telephonic Instrument to Screen for Cognitive Impairment in a Managed Care Population. Journal of Clinical Outcomes Management, , 419-429.
An analysis of data from 40 participants enrolled in a long-term study at the UCSD Alzheimer’s Disease Research Center (ADRC) found that "paper-and-pencil" cognitive skills tests administered to normal subjects averaging 75 years of age contained early signs of cognitive decline in those subjects who later developed Alzheimer’s disease. All participants were symptom-free when they took the test. The differences were quite subtle - only some performance measures were affected.
A three-year study of 48 healthy people from 60 to 80 years old, by New York University School of Medicine researchers, predicted which healthy elderly men and women would develop memory impairment based on scans of their brains. At the beginning of the study, everyone scored within the normal range on a battery of tests typically used to detect early loss of memory and other mental skills. However, PET scans revealed a reduction in glucose metabolism in an area of the brain called the entorhinal cortex among 12 people. Three years later, 11 of these people had experienced mild cognitive impairment and one had developed Alzheimer's disease. "Our work extends the use of PET scanning to identifying in normal aging subjects the earliest metabolic abnormalities that may lead to the memory losses referred to as mild cognitive impairment (MCI). The diagnosis of MCI carries a high risk for future Alzheimer's disease."
The study is published in the September 11 issue of The Proceedings of the National Academy of Sciences.
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