MCI

mild cognitive impairment

Why HIV-associated dementia occurs & implications for other disorders

October, 2012

A new understanding of why dementia sometimes occurs with HIV, even when treated, may also suggest a new approach to other neurological disorders, including age-related cognitive decline.

HIV-associated dementia occurs in around 30% of untreated HIV-positive patients. Surprisingly, it also is occasionally found in some patients (2-3%) who are being successfully treated for HIV (and show no signs of AIDS).

A new study may have the answer for this mystery, and suggest a solution. Moreover, the answer may have general implications for those experiencing cognitive decline in old age.

The study found that HIV, although it doesn’t directly infect neurons, tries to stop the development of BDNF. Long known to be crucial for memory and learning, the reduced production of mature BDNF results in axons and dendrites shortening — meaning connections between neurons are lost. That in turn, brings about the death of some neurons.

It seems that the virus interferes with the normal process of development in BDNF, whereby one form of it, called proBDNF, is cut by certain enzymes into a new form called mature BDNF. It is in this form that it has its beneficial effect on neuron growth. Unfortunately, in its earlier form it is toxic to neurons.

This imbalance in the proportions of mature BDNF and proBDNF also appears to occur as we age, and in depression. It may also be a risk factor in Parkinson's and Huntington's diseases.

However, these findings suggest a new therapeutic approach.

Compounds in green tea and chocolate may help protect brain cells

In which context, it is interesting to note another new study, which has been busy analyzing the effects on brain cells of 2000 compounds, both natural and synthetic. Of the 256 that looked to have protective effects, nine were related to epicatechin, which is found in cocoa and green tea leaves.

While we’ve been aware for some time of these positive qualities, the study specifically identified epicatechin and epigallocatechin gallate (EGCG) as being the most effective at helping protect neurons by inducing production of BDNF.

One of the big advantages these compounds have is in their ability to cross the blood-brain barrier, making them a good candidate for therapy.

While green tea, dark chocolate, and cocoa are particularly good sources, many fruits also have good levels, in particular, black grapes, blackberries, apples, cherries, pears, and raspberries. (see this University of Davis document (pdf) for more detail)

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Regular cocoa drinking helps those with MCI

September, 2012

Daily consumption of a high level of cocoa was found to improve cognitive scores, insulin resistance and blood pressure, in older adults with mild cognitive impairment.

Back in 2009, I reported briefly on a large Norwegian study that found that older adults who consumed chocolate, wine, and tea performed significantly better on cognitive tests. The association was assumed to be linked to the flavanols in these products. A new study confirms this finding, and extends it to older adults with mild cognitive impairment.

The study involved 90 older adults with MCI, who consumed either 990 milligrams, 520 mg, or 45 mg of a dairy-based cocoa drink daily for eight weeks. Their diet was restricted to eliminate other sources of flavanols (such as tea, red wine, apples and grapes).

Cognitive assessment at the end of this period revealed that, although scores on the MMSE were similar across all groups, those consuming higher levels of flavanol cocoa took significantly less time to complete Trail Making Tests A and B, and scored significantly higher on the verbal fluency test. Insulin resistance and blood pressure was also lower.

Those with the highest levels of flavanols did better than those on intermediate levels on the cognitive tests. Both did better than those on the lowest levels.

Changes in insulin resistance explained part, but not all, of the cognitive improvement.

One caveat: the group were generally in good health without known cardiovascular disease — thus, not completely representative of all those with MCI.

 

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Controlling diabetes important for slowing cognitive decline

August, 2012
  • Findings from a large, long-running study adds to growing evidence that poorly controlled diabetes is associated with faster cognitive decline.

The latest finding from the large, long-running Health, Aging, and Body Composition (Health ABC) Study adds to the evidence that preventing or controlling diabetes helps prevent age-related cognitive decline.

The study involves 3,069 older adults (70+), of whom 717 (23%) had diabetes at the beginning of the study in 1997. Over the course of the study, a further 159 developed diabetes. Those with diabetes at the beginning had lower cognitive scores, and showed faster decline. Those who developed diabetes showed a rate of decline that was between that faster rate and the slower rate of those who never developed diabetes.

Among those with diabetes, those who had higher levels of a blood marker called glycosylated hemoglobin had greater cognitive impairment. Higher levels of this blood marker reflect poorer control of blood sugar.

In other words, both duration and severity of diabetes are important factors in determining rate of cognitive decline in old age.

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Alzheimer's risk gene disrupts brain function in older women, but not men

August, 2012

A new study indicates that carrying the ‘Alzheimer’s gene’ may be a significant risk factor for women only.

While the ‘Alzheimer’s gene’ is relatively common — the ApoE4 mutation is present in around 15% of the population — having two copies of the mutation is, thankfully, much rarer, at around 2%. Having two copies is of course a major risk factor for developing Alzheimer’s, and it has been thought that having a single copy is also a significant (though lesser) risk factor. Certainly there is quite a lot of evidence linking ApoE4 carriers to various markers of cognitive impairment.

And yet, the evidence has not been entirely consistent. I have been puzzled by this myself, and now a new finding suggests a reason. It appears there are gender differences in responses to this gene variant.

The study involved 131 healthy older adults (median age 70), whose brains were scanned. The scans revealed that in older women with the E4 variant, brain activity showed the loss of synchronization that is typically seen in Alzheimer’s patients, with the precuneus (a major hub in the default mode network) out of sync with other brain regions. This was not observed in male carriers.

The finding was confirmed by a separate set of data, taken from the Alzheimer's Disease Neuroimaging Initiative database. Cerebrospinal fluid from 91 older adults (average age 75) revealed that female carriers had substantially higher levels of tau protein (a key Alzheimer’s biomarker) than male carriers or non-carriers.

It’s worth emphasizing that the participants in the first study were all cognitively normal — the loss of synchronization was starting to happen before visible Alzheimer’s symptoms appeared.

The findings suggest that men have less to worry about than women, as far as the presence of this gene is concerned. The study may also explain why more women than men get the disease (3 women to 2 men); it is not (although of course this is a factor) simply a consequence of women tending to live longer.

Whether or not these gender differences extend to carriers of two copies of the gene is another story.

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Exercise reduces Alzheimer's damage in brain

August, 2012

A mouse study provides more support for the value of exercise in preventing Alzheimer’s disease, and shows one of the ways in which it does so.

A study designed to compare the relative benefits of exercise and diet control on Alzheimer’s pathology and cognitive performance has revealed that while both are beneficial, exercise is of greater benefit in reducing Alzheimer’s pathology and cognitive impairment.

The study involved mice genetically engineered with a mutation in the APP gene (a familial risk factor for Alzheimer’s), who were given either a standard diet or a high-fat diet (60% fat, 20% carbohydrate, 20% protein vs 10% fat, 70% carbohydrate, 20% protein) for 20 weeks (from 2-3 to 7-8 months of age). Some of the mice on the high-fat diet spent the second half of that 20 weeks in an environmentally enriched cage (more than twice as large as the standard cage, and supplied with a running wheel and other objects). Others on the high-fat diet were put back on a standard diet in the second 10 weeks. Yet another group were put on a standard diet and given an enriched cage in the second 10 weeks.

Unsurprisingly, those on the high-fat diet gained significantly more weight than those on the standard diet, and exercise reduced that gain — but not as much as diet control (i.e., returning to a standard diet) did. Interestingly, this was not the result of changes in food intake, which either stayed the same or slightly increased.

More importantly, exercise and diet control were roughly equal in reversing glucose intolerance, but exercise was more effective than diet control in ameliorating cognitive impairment. Similarly, while amyloid-beta pathology was significantly reduced in both exercise and diet-control conditions, exercise produced the greater reduction in amyloid-beta deposits and level of amyloid-beta oligomers.

It seems that diet control improves metabolic disorders induced by a high-fat diet — conditions such as obesity, hyperinsulinemia and hypercholesterolemia — which affects the production of amyloid-beta. However exercise is more effective in tackling brain pathology directly implicated in dementia and cognitive decline, because it strengthens the activity of an enzyme that decreases the level of amyloid-beta.

Interestingly, and somewhat surprisingly, the combination of exercise and diet control did not have a significantly better effect than exercise alone.

The finding adds to the growing pile of evidence for the value of exercise in maintaining a healthy brain in later life, and helps explain why. Of course, as I’ve discussed on several occasions, we already know other mechanisms by which exercise improves cognition, such as boosting neurogenesis.

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Coffee helps prevent progression to dementia

July, 2012

A 4-year study of older adults has found that low levels of caffeine were linked to MCI progressing to dementia, apparently by mediating lower levels of anti-inflammatory proteins.

Following on from mouse studies, a human study has investigated whether caffeine can help prevent older adults with mild cognitive impairment from progressing to dementia.

The study involved 124 older adults (65-88) who were thoroughly cognitively assessed, given brain scans, and had a fasting blood sample taken. They were then followed for 2 to 4 years, during which their cognitive status was re-assessed annually. Of the 124 participants, 69 (56%) were initially assessed as cognitively normal (average age 73), 32 (26%) with MCI (average age 76.5), and 23 (19%) with dementia (average age 77). The age differences were significant.

Those with MCI on initial assessment showed significantly lower levels of caffeine in their blood than those cognitively healthy; levels in those with dementia were also lower but not significantly. Those initially healthy who developed MCI over the study period similarly showed lower caffeine levels than those who didn’t develop MCI, but again, due to the wide individual variability (and the relatively small sample size), this wasn’t significant. However, among those with MCI who progressed to dementia (11, i.e. a third of those with MCI), caffeine levels were so much lower that the results were significant.

This finding revealed an apparently critical level of caffeine dividing those who progressed to dementia and those who did not — more specifically, all of those who progressed to dementia were below this level, while around half of those who remained stable were at the level or above. In other words, low caffeine would seem to be necessary but not sufficient.

On the other hand (just to show that this association is not as simple as it appears), those already with dementia had higher caffeine levels than those with MCI who progressed to dementia.

The critical factor may have to do with three specific cytokines — GCSF, IL-10, and IL-6 — which all showed markedly lower levels in those converting from MCI to dementia. Comparison of the three stable-MCI individuals with the highest caffeine levels and the three with the lowest levels, and the three from the MCI-to-dementia group with comparable low levels, revealed that high levels of those cytokines were matched with high caffeine levels, while, in both groups, low caffeine levels were matched to low levels of those cytokines.

These cytokines are associated with inflammation — an established factor in cognitive decline and dementia.

The level of coffee needed to achieve the ‘magic’ caffeine level is estimated at around 3 cups a day. While caffeine can be found in other sources, it is thought that in this study, as in the mouse studies, coffee is the main source. Moreover, mouse research suggests that caffeine is interacting with an as yet unidentified component of coffee to boost levels of these cytokines.

This research has indicated that caffeine has several beneficial effects on the brain, including suppressing levels of enzymes that produce amyloid-beta, as well as these anti-inflammatory effects.

It’s suggested that the reason high levels of caffeine don’t appear to benefit those with dementia is because higher levels of these cytokines have become re-established, but this immune response would appear to come too late to protect the brain. This is consistent with other evidence of the importance of timing.

Do note that in mouse studies, the same benefits were not associated with decaffeinated coffee.

While this study has some limitations, the findings are consistent with previous epidemiologic studies indicating coffee/caffeine helps protect against cognitive impairment and dementia. Additionally, in keeping with the apparent anti-inflammatory action, a long-term study tracking the health and coffee consumption of more than 400,000 older adults recently found that coffee drinkers had reduced risk of dying from heart disease, lung disease, pneumonia, stroke, diabetes, infections, injuries and accidents.

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Cao, C., Loewenstein, D. a, Lin, X., Zhang, C., Wang, L., Duara, R., Wu, Y., et al. (2012). High Blood Caffeine Levels in MCI Linked to Lack of Progression to Dementia. Journal of Alzheimer’s disease : JAD, 30(3), 559–72. doi:10.3233/JAD-2012-111781

Freedman, N.D. et al. 2012. Association of Coffee Drinking with Total and Cause-Specific Mortality. N Engl J Med, 366, 1891-1904.

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Immune system may protect against Alzheimer's

July, 2012

New studies involving genetically-engineered mice and older adult humans support a connection between the immune system and cognitive impairment in old age.

A number of studies have come out in recent years linking age-related cognitive decline and dementia risk to inflammation and infection (put inflammation into the “Search this site” box at the top of the page and you’ll see what I mean). New research suggests one important mechanism.

In a mouse study, mice engineered to be deficient in receptors for the CCR2 gene — a crucial element in removing beta-amyloid and also important for neurogenesis — developed Alzheimer’s-like pathology more quickly. When these mice had CCR2 expression boosted, accumulation of beta-amyloid decreased and the mice’s memory improved.

In the human study, the expression levels of thousands of genes from 691 older adults (average age 73) in Italy (part of the long-running InCHIANTI study) were analyzed. Both cognitive performance and cognitive decline over 9 years (according to MMSE scores) were significantly associated with the expression of this same gene. That is, greater CCR2 activity was associated with lower cognitive scores and greater decline.

Expression of the CCR2 gene was also positively associated with the Alzheimer’s gene — meaning that those who carry the APOE4 variant are more likely to have higher CCR2 activity.

The finding adds yet more weight to the importance of preventing / treating inflammation and infection.

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[2960] Harries, L. W., Bradley-Smith R. M., Llewellyn D. J., Pilling L. C., Fellows A., Henley W., et al.
(2012).  Leukocyte CCR2 Expression Is Associated with Mini-Mental State Examination Score in Older Adults.
Rejuvenation Research. 120518094735004 - 120518094735004.

Naert, G. & Rivest S. 2012. Hematopoietic CC-chemokine receptor 2-(CCR2) competent cells are protective for the cognitive impairments and amyloid pathology in a transgenic mouse model of Alzheimer's disease. Molecular Medicine, 18(1), 297-313.

El Khoury J, et al. 2007. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nature Medicine, 13, 432–8.

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Omega-3 oil linked to lower level of Alzheimer's protein

June, 2012

A new study adds to growing evidence that higher levels of omega-3 fatty acids help protect against Alzheimer’s disease.

A new study, involving 1,219 dementia-free older adults (65+), has found that the more omega-3 fatty acids the person consumed, the lower the level of beta-amyloid in the blood (a proxy for brain levels). Consuming a gram of omega-3 more than the average per day was associated with 20-30% lower beta-amyloid levels. A gram of omega-3 equates to around half a fillet of salmon per week.

Participants provided information about their diet for an average of 1.2 years before their blood was tested for beta-amyloid. Other nutrients investigated —saturated fatty acids, omega-6 polyunsaturated fatty acids, mono-unsaturated fatty acid, vitamin E, vitamin C, beta-carotene, vitamin B12, folate and vitamin D — were not associated with beta-amyloid levels.

The results remained after adjusting for age, education, gender, ethnicity, amount of calories consumed and APOE gene status.

The findings are consistent with previous research associating higher levels of omega-3 and/or fish intake with lower risk of Alzheimer’s. Additionally, another recent study provides evidence that the brains of those with Alzheimer’s disease, MCI, and the cognitively normal, all have significantly different levels of omega-3 and omega-6 fatty acids. That study concluded that the differences were due to both consumption and metabolic differences.

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[2959] Gu, Y., Schupf N., Cosentino S. A., Luchsinger J. a, & Scarmeas N.
(2012).  Nutrient Intake and Plasma Β-Amyloid.
Neurology. 78(23), 1832 - 1840.

Cunnane, S.C. et al. 2012. Plasma and Brain Fatty Acid Profiles in Mild Cognitive Impairment and Alzheimer’s Disease. Journal of Alzheimer’s Disease, 29 (3), 691-697.

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Purpose in life protects against Alzheimer's disease

June, 2012
  • New results from a longitudinal study add to evidence that having a purpose and finding meaning in life protects against the harmful effects of Alzheimer’s pathology in the brain.

Here’s a different aspect to cognitive reserve. I have earlier reported on the first tranche of results from this study. Now new results, involving 246 older adults from the Rush Memory and Aging Project, have confirmed earlier findings that having a greater purpose in life may help protect against the brain damage wrought by Alzheimer’s disease.

Participants received an annual clinical evaluation for up to 10 years, which included detailed cognitive testing and neurological exams. They were also interviewed about their purpose in life, that is, the degree to which they derived meaning from life's experiences and were focused and intentional. After death (average age 88), their brains were examined for Alzheimer’s pathology.

Cognitive function, unsurprisingly, declined progressively with increased Alzheimer’s pathology (such as amyloid plaque and tau tangles). But ‘purpose in life’ modified this association, with higher levels of purposiveness reducing the effect of pathology on cognition. The effect was strongest for those with the greatest damage (especially tangles).

The analysis took into account depression, APOE gene status, and other relevant medical factors.

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Computer use and exercise combo reduce odds of MCI

June, 2012

Engaging in both moderate exercise and cognitively stimulating activities has an additive effect in reducing your risk of becoming cognitively impaired.

More findings from the long-running Mayo Clinic Study of Aging reveal that using a computer plus taking moderate exercise reduces your risk of mild cognitive impairment significantly more than you would expect from simply adding together these two beneficial activities.

The study involved 926 older adults (70-93), of whom 109 (12%) were diagnosed with MCI. Participants completed questionnaires on physical exercise and mental stimulation within the previous year. Computer use was targeted in this analysis because of its popularity as a cognitive activity, and because it was particularly associated with reduced odds of having MCI.

Among the cognitively healthy, only 20.1% neither exercised moderately nor used a computer, compared to 37.6% of those with MCI. On the other hand, 36% of the cognitively healthy both exercised and used a computer, compared to only 18.3% of those with MCI. There was little difference between the two groups as regards exercise but no computer use, or computer use but no exercise.

The analysis took into account calorie intake, as well as education, depression, and other health factors. Daily calorie intake was significantly higher in those with MCI compared to those without (respective group medians of 2100 calories vs 1802) — note that the median BMI was the same for the two groups.

Moderate physical exercise was defined as brisk walking, hiking, aerobics, strength training, golfing without a golf cart, swimming, doubles tennis, yoga, martial arts, using exercise machines and weightlifting. Light exercise included activities such as bowling, leisurely walking, stretching, slow dancing, and golfing with a cart. Mentally stimulating activities included reading, crafts, computer use, playing games, playing music, group and social and artistic activities and watching less television.

It should be noted that the assessment of computer activities was very basic. The researchers suggest that in future studies, both duration and frequency should be assessed. I would add type of activity, although that would be a little more difficult to assess.

Overall, the findings add yet more weight to the evidence for the value of physical exercise and mental stimulation in staving off cognitive impairment in old age, and add the twist that doing both is much better than doing either one alone.

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