mild cognitive impairment
A French study involving 6,626 older adults (65+) found that having optimal levels in more measures of cardiovascular health (nonsmoking, weight, diet, physical activity, cholesterol, blood glucose and blood pressure) was associated with lower dementia risk and slower rates of cognitive decline. Dementia risk and rates of cognitive decline lowered with each additional metric at the recommended optimal level.
The measures come from an American Heart Association seven-item checklist aimed at preventing cardiovascular disease.
New findings from the large, long-running Whitehall II study revealed that 50-year-olds who had blood pressure that was higher than normal but still below the usual threshold for treating hypertension, were at increased risk of developing dementia in later life.
This increased risk was seen even when they didn’t have other heart or blood vessel-related problems.
The study involved 8,639 people, of whom 32.5% were women. Participants were aged between 35-55 in 1985, and had their blood pressure measured in 1985, 1991, 1997 and 2003. 385 (4.5%) developed dementia by 2017.
Those who had a systolic blood pressure of 130 mmHg or more at the age of 50 had a 45% greater risk of developing dementia than those with a lower systolic blood pressure at the same age. This association was not seen at the ages of 60 and 70, and diastolic blood pressure was not linked to dementia.
Preliminary results from the Systolic Blood Pressure Intervention Trial (SPRINT) has found that aggressive lowering of systolic blood pressure produced significant reductions in the risk of MCI, and MCI/dementia.
The randomized clinical trial compared an intensive strategy with a systolic blood pressure goal of less than 120 mm Hg and a standard care strategy targeting a systolic blood pressure goal of less than 140 mm Hg. The study involved 9,361 hypertensive older adults (mean age 67.9).
The intensive treatment group had a 19% lower rate of new cases of MCI, and the combined outcome of MCI plus probable all-cause dementia was 15% lower. Serious adverse events of hypotension, syncope, electrolyte abnormalities, and acute kidney injury or acute renal failure occurred more frequently in the intensive-treatment group (4.7% vs 2.5%).
Participants were seen monthly for the first 3 months and every 3 months thereafter. Medications were adjusted on a monthly basis and lifestyle modification was encouraged. 30% of the participants were African American and 10% were Hispanic.
Preliminary results from 673 participants in the trial revealed that total white matter lesion (WML) volume increased in both treatment groups, but the increase was significantly less in the intensive treatment group. There was no significant difference in total brain volume change.
The findings were reported at the Alzheimer's Association International Conference (AAIC) 2018 in Chicago.
A long-running study involving 356 older adults (average age 78) found that those with high levels of arterial stiffness were 60% more likely to develop dementia during the next 15 years compared to those with lower levels.
Arterial stiffness is correlated with subclinical brain disease and cardiovascular risk factors, but adjusting for these factors didn't reduce the association between arterial stiffness and dementia — indicating that arterial stiffness and subclinical brain damage markers are independently related to dementia risk.
Arterial stiffening can be reduced by antihypertensive medication and perhaps also healthy lifestyle changes such as exercise. This study found that exercise at an average age of 73 was associated with lower arterial stiffness five years later.
A rat study found that hypertensive rats exhibited larger ventricles, decreased brain volume, and impaired fluid transport. It’s suggested that hypertension interferes with the clearance of macromolecules from the brain, such as amyloid-beta.
Samieri C, Perier M, Gaye B, et al. Association of Cardiovascular Health Level in Older Age With Cognitive Decline and Incident Dementia. JAMA. 2018;320(7):657–664. doi:10.1001/jama.2018.11499
Abell, J. et al. 2018. Association between systolic blood pressure and dementia in the Whitehall II cohort study: role of age, duration and threshold used to define hypertension. European Heart Journal. doi:10.1093/eurheartj/ehy288
 Cui, C., Sekikawa A., Kuller L. H., Lopez O. L., Newman A. B., Kuipers A. L., et al.
(2018). Aortic Stiffness is Associated with Increased Risk of Incident Dementia in Older Adults.
Journal of Alzheimer's Disease. 66(1), 297 - 306.
 Mortensen, K. Nygaard, Sanggaard S., Mestre H., Lee H., Kostrikov S., Xavier A. L. R., et al.
(2019). Impaired Glymphatic Transport in Spontaneously Hypertensive Rats.
Journal of Neuroscience. 39(32), 6365 - 6377.
Although first reported in 1816, the fact that the brain is surrounded by lymphatic vessels, which connect the brain and the immune system, was only rediscovered in 2015.
Lymphatic vessels are part of the body's circulatory system. In most of the body they run alongside blood vessels. They transport lymph, a colorless fluid containing immune cells and waste, to the lymph nodes. Blood vessels deliver white blood cells to an organ and the lymphatic system removes the cells and recirculates them through the body. The process helps the immune system detect whether an organ is under attack from bacteria or viruses or has been injured.
Since then, brain scans have indicated that our brains drain some waste out through lymphatic vessels, and could act as a pipeline between the brain and the immune system.
More recent research suggests the vessels are vital to the brain's ability to cleanse itself. When a compound was used to improve the flow of waste from the brain to the lymph nodes in the neck of aged mice, their ability to learn and remember improved dramatically.
Moreover, obstructing the vessels in mice worsened the accumulation of harmful amyloid plaques in the brain.
 Da Mesquita, S., Louveau A., Vaccari A., Smirnov I., R. Cornelison C., Kingsmore K. M., et al.
(2018). Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease.
Nature. 560(7717), 185 - 191.
Absinta, Ha et al. Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI, October 3, 2017, eLife: 10.7554/eLife.29738
A study involving 2,000 healthy older adults (average age 78) found that mentally stimulating activities were linked to a lower risk or delay of MCI, and that the timing and number of these activities may also play a role.
During the study, 532 participants developed MCI.
Using a computer in middle-age (50-65) was associated with a 48% lower risk of MCI, while using a computer in later life was associated with a 30% lower risk, and using a computer in both middle-age and later life was associated with a 37% lower risk.
Engaging in social activities, like going to movies or going out with friends, or playing games, like doing crosswords or playing cards, in both middle-age and later life were associated with a 20% lower risk of developing MCI.
Craft activities were associated with a 42% lower risk, but only in later life.
Those who engaged in two activities were 28% less likely to develop MCI than those who took part in no activities, while those who took part in three activities were 45% less likely, those with four activities 56% percent less likely and those with five activities were 43% less likely.
It should be noted that activities in middle-age were assessed by participants’ memory many years later.
Data from the PROTECT online platform, involving 19,000 healthy older adults (50-96), found that the more regularly older adults played puzzles such as crosswords and Sudoku, the better they performed on tasks assessing attention, reasoning and memory.
In some areas the improvement was quite dramatic, for example, on measures of problem-solving, people who regularly do these puzzles performed equivalent to an average of eight years younger compared to those who don't.
A meta-analysis of 32 randomized controlled trials with 3,624 older adults with or without cognitive impairment has concluded that mind-body exercises, especially tai chi and dance mind-body exercise, help improve global cognition, cognitive flexibility, working memory, verbal fluency, and learning in older adults.
Krell-Roesch, J., Syrjanen, J. A., Vassilaki, M., Machulda, M. M., Mielke, M. M., Knopman, D. S., … Geda, Y. E. (2019). Quantity and quality of mental activities and the risk of incident mild cognitive impairment. Neurology, 93(6), e548. https://doi.org/10.1212/WNL.0000000000007897
Brooker, H., Wesnes, K. A., Ballard, C., Hampshire, A., Aarsland, D., Khan, Z., … Corbett, A. (2019). The relationship between the frequency of number-puzzle use and baseline cognitive function in a large online sample of adults aged 50 and over. International Journal of Geriatric Psychiatry, 34(7), 932–940. https://doi.org/10.1002/gps.5085
Brooker, H., Wesnes, K. A., Ballard, C., Hampshire, A., Aarsland, D., Khan, Z., … Corbett, A. (2019). An online investigation of the relationship between the frequency of word puzzle use and cognitive function in a large sample of older adults. International Journal of Geriatric Psychiatry, 34(7), 921–931. https://doi.org/10.1002/gps.5033
Wu, C., Yi, Q., Zheng, X., Cui, S., Chen, B., Lu, L., & Tang, C. (2019). Effects of Mind-Body Exercises on Cognitive Function in Older Adults: A Meta-Analysis. Journal of the American Geriatrics Society, 67(4), 749–758. https://doi.org/10.1111/jgs.15714
Data from the large, long-running U.S. Health and Retirement Study found that healthy cognition characterized most of the people with at least a college education into their late 80s, while those who didn’t complete high school had good cognition up until their 70s.
The study found that those who had at least a college education lived a much shorter time with dementia than those with less than a high school education: an average of 10 months for men and 19 months for women, compared to 2.57 years (men) and 4.12 years (women).
The data suggests that those who graduated high school can expect to live (on average) at least 70% of their remaining life after 65 with good cogntion, compared to more than 80% for those with a college education, and less than 50% for those who didn't finish high school.
The analysis was based on a sample of 10,374 older adults (65+; average age 74) in 2000 and 9,995 in 2010.
https://academic.oup.com/psychsocgerontology/article/73/suppl_1/S20/4971564 (open access)
Data from around 196,000 subscribers to Lumosity online brain-training games found that higher levels of education were strong predictors of better cognitive performance across the 15- to 60-year-old age range of their study participants, and appear to boost performance more in areas such as reasoning than in terms of processing speed.
Differences in performance were small for test subjects with a bachelor's degree compared to those with a high school diploma, and moderate for those with doctorates compared to those with only some high school education.
But people from lower educational backgrounds learned novel tasks nearly as well as those from higher ones.
Data from more than 1,000 men participating in the Vietnam Era Twin Study of Aging revealed that their cognitive ability at age 20 was a stronger predictor of cognitive function later in life than other factors, such as higher education, occupational complexity or engaging in late-life intellectual activities.
All of the men, now in their mid-50s to mid-60s, took the Armed Forces Qualification Test at an average age of 20. The same test of general cognitive ability (GCA) was given in late midlife, plus assessments in seven cognitive domains.
GCA at age 20 accounted for 40% of the variance in the same measure at age 62, and approximately 10% of the variance in each of the seven cognitive domains. Lifetime education, complexity of job and engagement in intellectual activities each accounted for less than 1% of variance at average age 62.
The findings suggest that the impact of education, occupational complexity and engagement in cognitive activities on later life cognitive function simply reflects earlier cognitive ability.
The researchers speculated that the role of education in increasing GCA takes place primarily during childhood and adolescence when there is still substantial brain development.
 Crimmins, E. M., Saito Y., Kim J. Ki, Zhang Y. S., Sasson I., & Hayward M. D.
(2018). Educational Differences in the Prevalence of Dementia and Life Expectancy with Dementia: Changes from 2000 to 2010.
The Journals of Gerontology: Series B. 73(suppl_1), S20 - S28.
Guerra-Carrillo, B., Katovich, K., & Bunge, S. A. (2017). Does higher education hone cognitive functioning and learning efficacy? Findings from a large and diverse sample. PLOS ONE, 12(8), e0182276. https://doi.org/10.1371/journal.pone.0182276
 Kremen, W. S., Beck A., Elman J. A., Gustavson D. E., Reynolds C. A., Tu X. M., et al.
(2019). Influence of young adult cognitive ability and additional education on later-life cognition.
Proceedings of the National Academy of Sciences. 116(6), 2021.
Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), involving 230 cognitively normal individuals and 394 individuals with diagnosed with MCI on the basis of one episodic test, has found that performance on two tests markedly improved the identification of those whose MCI was more serious.
MCI can be a step on the road to Alzheimer's, but it can also be a reversible condition, and it’s obviously helpful to be able to distinguish the two.
The study compared those with MCI whose memory performance was impaired only in one (story recall) or two (story recall and word list recall) tests. Those who performed poorly in both showed Alzheimer's biomarkers in the cerebrospinal fluid that more closely resembled Alzheimer's patients than those who only did poorly in one test. Moreover, they showed faster brain atrophy in the medial temporal lobes.
Alzheimer's disease was diagnosed within the three-year study period in around half of the participants who performed poorly in both tests, but in only 16% of those with a poor performance on one test.
An Argentinian study involving 1,414 adults with high blood pressure has concluded that the clock drawing test for detecting cognitive dysfunction should be conducted routinely in patients with high blood pressure
A higher prevalence of cognitive impairment was found with the clock drawing test (36%) compared to the MMSE (21%). Three out ten patients who had a normal MMSE score had an abnormal clock drawing result. The disparity in results between the two tests was greatest in middle aged patients.
The clock drawing test is particularly useful for evaluating executive functions, which are the cognitive function most likely to be damaged by untreated high blood pressure.
The clock drawing test involves being given a piece of paper with a 10 cm diameter circle on it, and having to write the numbers of the clock in the correct position inside the circle and then draw hands on the clock indicating the time "twenty to four".
The average blood pressure was 144/84 mmHg, average age was 60 years, and 62% were women.
The findings were presented at ESC Congress 2018.
Those suspected of cognitive impairment often undergo repeated cognitive testing over time — indeed it is the change over time that is most diagnostic. However, most cognitive functions get better with practice. A new study involving 995 middle- to late-middle-aged men has found that, indeed, there were significant practice effects in most cognitive domains, and diagnoses of MCI doubled from 4.5 to 9% after correcting for practice effects.
A large study involving 1820 adults (44+), of whom 568 were cognitively healthy, 885 had MCI, and 367 mild Alzheimer's, found that verb fluency worsened at each stage of cognitive decline, and worse scores in verb fluency task were significantly related to development of MCI, and progression from MCI to dementia. Worsening verb fluency was also associated with a faster decline to MCI, but not to faster progression from MCI to dementia.
Most previous research with word fluency has used category and letter fluency tasks (which demand generating names) rather than verb fluency, but verb fluency is more cognitively demanding than generating names, and may thus be a more sensitive tool.
A brief, simple number naming test has been found to differentiate between cognitively healthy older adults and those with MCI or Alzheimer's.
The King-Devick (K-D) test is a one- to two-minute rapid number naming test that has previously been found useful in the detection of concussion, as well as in detecting level of impairment in other neurological conditions such as Parkinson's disease and multiple sclerosis. The K-D test can be quickly administered by non-professional office staff on either a tablet (iPad) or in a paper version.
The test accurately distinguished the controls from the cognitively impaired individuals more than 90% of the time.
The study involved 206 older adults, including 135 cognitively healthy individuals, 39 people with MCI, and 32 Alzheimer's patients.
The test will need to be validated in larger samples.
A number of studies have shown that people’s own subjective impressions of memory problems should not be discounted, but they shouldn’t be given too much weight either, since many people are over-anxious nowadays about their prospects of dementia. But there is a further complication to this issue, which is that being unaware of one’s own memory problems is typical of Alzheimer's.
Anosognosia is the name for this condition of not being able to recognize one’s memory problems.
A study involving 450 patients who experienced mild memory deficits, but were still capable of taking care of themselves, assessed this awareness by asking both the patients and their close relatives about the patient’s cognitive abilities. Anosognosia was diagnosed when a patient reported having no cognitive problems but the family member reported significant difficulties.
The study found that those suffering from anosognosia had impaired brain metabolic function and higher rates of amyloid deposition. Two years later, they were more likely to have developed dementia.
A study involving 1,062 older adults (55-90), including 191 people with Alzheimer's disease, 499 with MCI and 372 healthy controls, found that those with anosognosia had reduced glucose uptake in specific brain regions. Glucose uptake is impaired in Alzheimer's disease.
The hippocampus, one of the earliest brain regions affected in Alzheimer's, has a number of important memory functions. One of these is relational memory — the hippocampus can bind together pieces of information stored in different parts of the brain, so that, for example, you can remember the name when you see the associated face.
A new cognitive test that assesses relational memory has been found to be effective in distinguishing cognitive impairment that reflects very early mild Alzheimer's from normal aging.
The test involves a circle divided into three parts, each having a unique design. After studying a circle, participants needed to pick its exact match from a series of 10 circles, presented one at a time.
People with very mild Alzheimer's disease did worse overall on the task than those in the healthy aging group, who, in turn, did worse than a group of young adults. Moreover, those with Alzheimer's were particularly susceptible to interference from intervening lure stimuli. Including this in the analysis improved the test’s ability to differentiate between those who did and those who did not have Alzheimer's. It also provides evidence that Alzheimer's is qualitatively different from normal age-related cognitive decline, not simply an extension of it.
The study involved 90 participants, including 30 young adults, 30 cognitively healthy older adults, and 30 with very early Alzheimer's.
 Vuoksimaa, E., McEvoy L. K., Holland D., Franz C. E., Kremen W. S., & Initiative for. the Alzhei
(2018). Modifying the minimum criteria for diagnosing amnestic MCI to improve prediction of brain atrophy and progression to Alzheimer’s disease.
Brain Imaging and Behavior.
 Elman, J. A., Jak A. J., Panizzon M. S., Tu X. M., Chen T., Reynolds C. A., et al.
(2018). Underdiagnosis of mild cognitive impairment: A consequence of ignoring practice effects.
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring. 10, 372 - 381.
Alegret M, Peretó M, Pérez A, Valero S, Espinosa A, Ortega G, Hernández I, Mauleón A, Rosende-Roca M, Vargas L, Rodríguez-Gómez O, Abdelnour C, Berthier ML, Bak TH, Ruiz A, Tárraga L, Boada M. The Role of Verb Fluency in the Detection of Early Cognitive Impairment in Alzheimer's Disease Journal of Alzheimer's Disease 2018.
 Galetta, K. M., Chapman K. R., Essis M. D., Alosco M. L., Gillard D., Steinberg E., et al.
(2017). Screening Utility of the King-Devick Test in Mild Cognitive Impairment and Alzheimer Disease Dementia.
Alzheimer Disease & Associated Disorders. 31(2), 152.
 Therriault, J., Ng K. Pin, Pascoal T. A., Mathotaarachchi S., Kang M. Su, Struyfs H., et al.
(2018). Anosognosia predicts default mode network hypometabolism and clinical progression to dementia.
Neurology. 90(11), e932.
 Gerretsen, P., Chung J. Ku, Shah P., Plitman E., Iwata Y., Caravaggio F., et al.
(2017). Anosognosia Is an Independent Predictor of Conversion From Mild Cognitive Impairment to Alzheimer’s Disease and Is Associated With Reduced Brain Metabolism.
The Journal of Clinical Psychiatry. 78(9), 1187 - 1196.
Monti, J. M., Balota, D. A., Warren, D. E., & Cohen, N. J. (2014). Very mild Alzheimer׳s disease is characterized by increased sensitivity to mnemonic interference. Neuropsychologia, 59, 47–56. https://doi.org/10.1016/j.neuropsychologia.2014.04.007
A review of 34 longitudinal studies, involving 71,244 older adults, has concluded that depression is associated with greater cognitive decline.
The study included people who presented with symptoms of depression as well as those that were diagnosed as clinically depressed, but excluded any who were diagnosed with dementia at the start of study.
Previous research has found that depression is associated with an increased dementia risk.
The researchers recommend that preventative measures such as exercising, practicing mindfulness, and undertaking recommended therapeutic treatments, such as Cognitive Behaviour Therapy, might help protect cognitive health.
While the review included some studies into anxiety, the numbers were insufficient to draw a conclusion.
 John, A., Patel U., Rusted J., & Richards M.
(Submitted). Affective problems and decline in cognitive state in older adults: a systematic review and meta-analysis.
| Psychological Medicine. 49(3), 353 - 365.
A small study has found that a 12-week exercise program significantly improved cognition in both older adults with MCI and those who were cognitively healthy, but that effect on blood flow in the brain was different in these two groups.
While the exercise increased cerebral blood flow in the frontal cortex of those in the healthy group, those with MCI experienced decreases in cerebral blood flow. It has been speculated that the brain responds to early difficulties by increasing cerebral blood flow. This suggests that exercise may have the potential to reduce this compensatory blood flow and improve cognitive efficiency in those who are in the very early stages of Alzheimer's Disease.
The exercise training program consisted of four 30-minute sessions of moderate-intensity treadmill walking per week.
Both working memory and verbal fluency were tested (using the Rey Auditory Verbal Learning Test, and the Controlled Oral Word Association Test).
Changes in cerebral blood flow were measured in specific brain regions that are known to be involved in the pathogenesis of Alzheimer's disease, including the insula, the anterior cingulate cortex, and the inferior frontal gyrus.
Among those with MCI, decreased blood flow in the left insula and anterior cingulate cortex was strongly associated with improved verbal fluency.
Alfini, A. J. et al. 2019. Resting Cerebral Blood Flow After Exercise Training in Mild Cognitive Impairment. Journal of Alzheimer's Disease, 67 (2), 671-684.
A clinical trial involving 9361 older adults (50+) with hypertension but without diabetes or history of stroke has found that intensive control of blood pressure significantly reduced the risk of developing mild cognitive impairment.
While there was also a 15% reduction in dementia, this result did not reach statistical significance. This may have been due to the small number of new cases of dementia in the study groups.
Participants were randomly assigned to a systolic blood pressure goal of either less than 120 mm HG (intensive treatment) or less than 140 mm HG (standard treatment). They were then classified after five years as having no cognitive impairment, MCI or probable dementia.
The trial was stopped early due to its success in reducing cardiovascular disease. As a result, participants were on intensive blood pressure lowering treatment for a shorter period than originally planned. This impacted the number of cases of dementia occurring.
Hypertension affects more than half of Americans over age 50 and more than 75% of those older than 65.
The SPRINT MIND Investigators for the SPRINT Research Group. (2019). Effect of Intensive vs Standard Blood Pressure Control on Probable Dementia: A Randomized Clinical Trial. JAMA, 321(6), 553–561.
The APOE gene, the strongest genetic risk factor for Alzheimer’s disease, is known to be involved in cholesterol and lipid metabolism. Now the largest ever genetic study of Alzheimer’s disease, using DNA from more than 1.5 million people, has identified 90 points across the genome that were associated with an increased risk of both cardiovascular disease and Alzheimer’s disease.
The study focused on specific risk factors for heart disease (e.g., high BMI, type 2 diabetes, high cholesterol) to see if any were genetically related to Alzheimer’s risk. It was found that only those genes involved in lipid metabolism also related to Alzheimer's risk.
Six of the 90 regions had very strong effects on Alzheimer’s and heightened blood lipid levels, including several points within the CELF1/MTCH2/SPI1 region on chromosome 11 that was previously linked to the immune system.
The same genetic risk factors were also more common in people with a family history of Alzheimer’s, even though they had not themselves developed dementia or MCI.
The findings suggest that cardiovascular and Alzheimer's risk co-occur because of a shared genetic basis.
They also suggest a therapeutic target — namely, pathways involved in lipid metabolism.
Broce I, Karch C, Desikan R, et al. Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer's disease. Acta Neuropathologica, published online Nov. 9, 2018.
Data from 1,215 older adults, of whom 173 (14%) were African-American, has found that, although brain scans showed no significant differences between black and white participants, cerebrospinal fluid (CSF) showed significantly lower levels of the brain protein tau in African-Americans.
While both groups showed the same (expected) pattern of higher tau levels being associated with greater chance of cognitive impairment, the absolute amounts of tau protein were consistently lower in African-Americans.
However, when APOE status was taken into account, it was found that those who held the low-risk variants of the “Alzheimer’s gene” had similar levels of tau, regardless of race. It was only African-Americans with the APOE4 gene variant that showed lower levels of tau.
This suggests that the APOE4 risk factor has different effects in African-Americans compared to non-Hispanic white Americans, and points to the need for more investigation into how Alzheimer’s develops in various populations.
Interestingly, another study, using data from 1798 patients (of whom 1690 were white), found that there was a strong gender difference in the association between APOE status and tau levels in the CSF.
Previous research has shown that the link between APOE4 and Alzheimer's is stronger in women than men. This study points to a connection with tau levels, as there was no gender difference in the association between APOE and amyloid-beta levels, amyloid plaques, or tau tangles.
Morris JC, Schindler SE, McCue LM, et al. Assessment of Racial Disparities in Biomarkers for Alzheimer Disease. JAMA Neurol. Published online January 07, 2019. doi:10.1001/jamaneurol.2018.4249
Hohman TJ, Dumitrescu L, Barnes LL, et al. Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau. JAMA Neurol. 2018;75(8):989–998. doi:10.1001/jamaneurol.2018.0821
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