brain atrophy

Genes linked to Alzheimer's

  • Very large study finds 5 new genes linked to increased Alzheimer's risk.
  • A rare gene variant that protects APOE4 gene carriers from getting Alzheimer's has been identified.
  • Two large surveys found that verbal recall score was significantly affected by TOMM40 genotype. TOMM40 is adjacent to APOE on their chromosome.
  • A study found that TOMM40's effect on Alzheimer's depends on parental history.
  • Data from three very large studies has produced a tool for assessing an individual's genetic risk for developing Alzheimer's, based on 31 genetic markers.
  • A small study found that, of the top 9 genes that affect Alzheimer's risk, excluding the APOE gene, only 2 affect brain atrophy.
  • A new gene variant that is associated with greater amyloid plaque than APOE4 has been identified.

Five new risk genes for Alzheimer's disease

Genetic data from more than 94,000 individuals has revealed five new risk genes for Alzheimer's disease, and confirmed 20 known others. The new genes are: IQCK, ACE, ADAM10, ADAMTS1 and WWOX.

The findings support developing evidence that groups of genes associated with specific biological processes, such as cell trafficking, lipid transport, inflammation and the immune response, are "genetic hubs" that are an important part of the disease process.

The study also suggests that variants affecting APP and amyloid beta protein processing are associated with both early-onset autosomal dominant Alzheimer's and with late onset Alzheimer's. In addition, for the first time, the study implicated a genetic link to tau binding proteins.

The findings follow on from a 2013 report.

https://www.eurekalert.org/pub_releases/2019-02/nioa-dsu022719.php

Gene variant found that protects against Alzheimer's

A large study involving families that had a large number of resilient individuals (those who carried the APOE4 gene but remained healthy into advanced age) has found that the resilient subjects shared a variant in the RAB10 gene while those who got the disease did not share that genetic variant.

https://www.eurekalert.org/pub_releases/2017-11/byu-rig112917.php

Gene linked to Alzheimer's gene affects age-related cognitive decline

TOMM40 and APOE genes are adjacent to each other on chromosome 19, and have sometimes been used as proxies for one another in genetic studies. TOMM40 has largely been thought of as a “sidekick” to ApoE4. But new research suggests it may have a stronger role.

Data from two large surveys — the U.S. Health and Retirement Study and the English Longitudinal Study of Ageing — found that verbal recall score was significantly affected by TOMM40 genotype.

The researchers examined 1.2 million gene variations across the human genome. TOMM40 was the only one with a strong link to declines in immediate recall and level of delayed recall. APOE4 also was linked but not as strongly.

To test immediate recall, an interviewer read a list of 10 nouns and then asked the participant to repeat the words back immediately. For delayed recall, the interviewer waited five minutes and then asked the participant to recall the list. Test scores ranged from 0 to 10. The average score for immediate recall was 5.7 words out of 10, and the delayed recall scoring average was 4.5 words out of 10. A large gap between the two sets of scores can signal the development of Alzheimer's or some other form of dementia.

Those who had received a likely diagnosis of dementia or a dementia-like condition were excluded from the study.

https://www.eurekalert.org/pub_releases/2017-09/uosc-it091417.php

Family history of Alzheimer's may alter gene that increases risk

There have been conflicting findings about whether the gene, TOMM40 (Translocase of Outer Mitochondrial Membrane-40kD) increases the risk for Alzheimer's. A new study, however, has found that its impact on memory and dementia risk depends on two other factors: parental history of Alzheimer's, and the length of a specific section of the gene.

In the study, late middle-aged people with a family history (parent with Alzheimer’s) and longer version of the gene had twice as much memory loss up to 10 years later as someone with a family history and a short version of the gene. A similar but stronger finding was seen in a group of older adults.

https://www.eurekalert.org/pub_releases/2017-05/isu-fho051917.php

Multiple genetic markers combine to estimate Alzheimer's risk

Genotype data from three very large studies has enabled researchers to construct a test that can be used to calculate any individual’s yearly risk for onset of Alzheimer's. The polygenic hazard score (PHS) is based on 31 genetic markers.

Those with the highest PHS (top 10%) were more than three times more likely to develop Alzheimer's than those with the lowest PHS, and to do so more than 10 years earlier.

In people with the high-risk version of ApoE, those ranked in the top 10% of risk on the new test got Alzheimer’s at an average age of 84 years, compared with 95 years for those ranked in the lowest 10%.

The study also demonstrates that, aside from ApoE, there are thousands of background genetic variations that each have a tiny influence on Alzheimer’s risk, but whose cumulative influence is substantial.

But note that this doesn’t tell us that it’s all about genes! Lifestyle factors are still very important in determining whether you actually get Alzheimer's.

https://www.eurekalert.org/pub_releases/2017-03/p-mgm031317.php

https://www.theguardian.com/society/2017/mar/22/new-alzheimers-test-can-predict-age-when-disease-will-appear

Two Alzheimer's risk genes linked to brain atrophy

A study involving 50 older adults (50+) with no cognitive difficulties and 90 who had been diagnosed with MCI has examined the top nine genetic variants associated with Alzheimer's risk, excluding the APOe4 gene, to find which of them was associated with atrophy in the cortex and hippocampus.

Only ABCA7 and MA4A6A were associated with brain atrophy.

http://www.eurekalert.org/pub_releases/2015-12/iu-tar122315.php

New gene linked to amyloid beta plaque buildup

A study involving nearly 500 individuals has found that a variant of the IL1RAP gene was associated with higher rates of amyloid plaque buildup in the brains of Alzheimer's patients and older adults at risk for the disease, and its effect on amyloid buildup was stronger than that of APOE4.

IL1RAP codes for the key immune signaling factor Interleukin-1 Receptor Accessory Protein, which plays a central role in the activity of microglia, the immune system cells that clear up waste products such as plaques and tangles.

Additionally, the IL1RAP variant was associated with:

  • a lower level of microglial activity
  • greater atrophy of the temporal cortex
  • faster cognitive decline
  • greater likelihood of progression from MCI to Alzheimer's.

http://www.eurekalert.org/pub_releases/2015-10/iu-rin100515.php

Reference: 

[4419] Kunkle, B. W., & et al
(Submitted).  Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing | Nature Genetics.

[3586] Lambert, J-C., Ibrahim-Verbaas C. A., Harold D., Naj A. C., Sims R., Bellenguez C., et al.
(2013).  Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease.
Nature Genetics. 45(12), 1452 - 1458.

[4420] Ridge, P. G., Karch C. M., Hsu S., Arano I., Teerlink C. C., Ebbert M. T. W., et al.
(2017).  Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer’s disease resilience.
Genome Medicine. 9(1), 100.

[4422] Arpawong, T. E., Pendleton N., Mekli K., McArdle J. J., Gatz M., Armoskus C., et al.
(2017).  Genetic variants specific to aging-related verbal memory: Insights from GWASs in a population-based cohort.
PLOS ONE. 12(8), e0182448.

[4423] Willette, A. A., Webb J. L., Lutz M. W., Bendlin B. B., Wennberg A. M. V., Oh J. M., et al.
(2017).  AD FAMILY HISTORY MODULATES EFFECTS OF TOMM40 ‘523’ POLY-T ON MTL ATROPHY AND HYPOMETABOLISM IN PRECLINICAL AND AD COHORTS.
Alzheimer's & Dementia: The Journal of the Alzheimer's Association. 13(7), P54 - P55.

[4424] Desikan, R. S., Fan C. Chieh, Wang Y., Schork A. J., Cabral H. J., L. Cupples A., et al.
(2017).  Genetic assessment of age-associated Alzheimer disease risk: Development and validation of a polygenic hazard score.
PLOS Medicine. 14(3), e1002258.

[4412] Ramirez, L. M., Goukasian N., Porat S., Hwang K. S., Eastman J. A., Hurtz S., et al.
(2016).  Common variants in ABCA7 and MS4A6A are associated with cortical and hippocampal atrophy.
Neurobiology of Aging. 39, 82 - 89.

[4425] Ramanan, V. K., Risacher S. L., Nho K., Kim S., Shen L., McDonald B. C., et al.
(2015).  GWAS of longitudinal amyloid accumulation on 18F-florbetapir PET in Alzheimer’s disease implicates microglial activation gene IL1RAP.
Brain. 138(10), 3076 - 3088.

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Smoking, hypertension, diabetes & obesity each linked to poor brain health

  • A large study has found that smoking, high blood pressure, diabetes, and obesity are each linked to more brain atrophy, and damage to white matter.
  • The more of these you have, the greater the shrinkage and damage.

Brain scans of 9,772 people aged 44 to 79, who were enrolled in the UK Biobank study, have revealed that smoking, high blood pressure, high pulse pressure, diabetes, and high BMI — but not high cholesterol — were all linked to greater brain shrinkage, less grey matter and less healthy white matter.

Smoking, high blood pressure, and diabetes were the most important factors, but there was also a compound effect, with the number of vascular risk factors being associated with greater damage to the brain. On average, those with the highest vascular risk had nearly 3% less volume of grey matter, and one-and-a-half times the damage to their white matter, compared to people who had the lowest risk.

The brain regions affected were mainly those involved in ‘higher-order’ thinking, and those known to be affected early in the development of dementia.

The associations were as strong for middle-aged adults as for older ones, suggesting the importance of tackling these factors early.

While the effect size was small, the findings emphasize how vulnerable the brain is to vascular factors even in relatively healthy adults. This also suggests the potential of lifestyle changes for fighting cognitive decline.

Although this study didn't itself examine cognitive performance in its participants, other studies have shown links between cognitive impairment and vascular risk factors, particularly diabetes, obesity, hypertension, and smoking.

https://www.eurekalert.org/pub_releases/2019-03/esoc-shb030719.php

Cognitive decline in type 2 diabetes linked to white matter hyperintensities

While type 2 diabetes has been associated with cognitive problems, the mechanism has been unclear. Now a study involving 93 people with type 2 diabetes has found that greater white matter hyperintensities (indicative of cerebral small vessel disease) were associated with decreased processing speed (but not with memory or executive function).

https://www.eurekalert.org/pub_releases/2018-09/w-rem091818.php

Reference: 

Cox, Simon R. et al. 2019. Associations between vascular risk factors and brain MRI indices in UK Biobank. European Heart Journal. doi:10.1093/eurheartj/ehz100

[4395] Mankovsky, B., Zherdova N., van den Berg E., Biessels G.-J., & de Bresser J.
(2018).  Cognitive functioning and structural brain abnormalities in people with Type 2 diabetes mellitus.
Diabetic Medicine. 35(12), 1663 - 1670.

 

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Smell tests provide early evidence of dementia

  • It seems clear now that a substantial decline in sense of smell is a very early sign of developing MCI and Alzheimer's.
  • Several tests have been developed to assess this.
  • It should always be remembered that there is substantial difference between individuals in their 'natural' sense of smell, and this needs to be taken into account in any test.

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).

Smell test improves accuracy of MCI & Alzheimer's diagnosis

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.

A new smell test

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:

  • In the OPID (Odor Percept IDentification)-10 test, participants are presented with 10 odors (menthol, clove, leather, strawberry, lilac, pineapple, smoke, soap, grape, lemon) for two seconds each. They are then asked whether the scent is familiar and given a choice of four of the 10 words from which are asked to pick the best one that describes the odor.
  • The Odor Awareness Scale (OAS) assesses their overall attention to environmental odors and how they are affected emotionally and behaviorally by scents.
  • The OPID-20 test includes an additional 10 odors (banana, garlic, cherry, baby powder, grass, fruit punch, peach, chocolate, dirt, orange). Participants are first asked whether a presented odor was included in the OPID-10 test and then asked which word best describes the odor. Their ability to remember odors from the first test determines their POEM (Percepts of Odor Episodic Memory) score.
  • In the Odor Discrimination (OD) test, participants are presented with two consecutive odors and asked whether they were different or the same, a process that is repeated 12 times with different paired scents.

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.

Validation of UPSIT

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, UPSIT was 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.

https://www.eurekalert.org/pub_releases/2016-12/uops-psc122016.php

https://www.eurekalert.org/pub_releases/2016-11/mgh-atr111416.php

http://www.eurekalert.org/pub_releases/2016-07/cumc-stm072516.php

Reference: 

[4209] Quarmley, M., Moberg P. J., Mechanic-Hamilton D., Kabadi S., Arnold S. E., Wolk D. A., et al.
(2017).  Odor Identification Screening Improves Diagnostic Classification in Incipient Alzheimer’s Disease.
Journal of Alzheimer's Disease. 55(4), 1497 - 1507.

[4210] Dhilla, A. Alefiya, Asafu-Adjei J., Delaney M. K., Kelly K. E., Gomez-Isla T., Blacker D., et al.
(2016).  Episodic memory of odors stratifies Alzheimer biomarkers in normal elderly.
Annals of Neurology. 80(6), 846 - 857.

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.

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Different kinds of physical activity improve brain volume & cut Alzheimer's risk

  • A large long-running study adds to growing evidence that higher levels of physical activity reduce brain atrophy and Alzheimer's risk, and shows that many types of aerobic activity are beneficial.

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.

http://www.eurekalert.org/pub_releases/2016-03/ip-dko030916.php

http://www.eurekalert.org/pub_releases/2016-03/uops-bmc031016.php

Reference: 

[4180] Raji, C. A., Merrill D. A., Eyre H., Mallam S., Torosyan N., Erickson K. I., et al.
(2016).  Longitudinal Relationships between Caloric Expenditure and Gray Matter in the Cardiovascular Health Study.
Journal of Alzheimer's disease: JAD.

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Omega 3 levels affect whether B vitamins can slow brain's decline

  • B vitamins can help many older adults with mild cognitive impairment, but only if they have good levels of omega-3 fatty acids.

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.

http://www.eurekalert.org/pub_releases/2016-01/uoo-ola011916.php

Reference: 

[4065] Oulhaj, A., Jernerén F., Refsum H., A. Smith D., & de Jager C. A.
(2016).  Omega-3 Fatty Acid Status Enhances the Prevention of Cognitive Decline by B Vitamins in Mild Cognitive Impairment.
Journal of Alzheimer's Disease. 50(2), 547 - 557.

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Alzheimer's disease consists of 3 distinct subtypes

  • A very small study points to three subtypes of Alzheimer's disease, each of which seems to be associated with:
    • different physiological abnormalities
    • different causes and risk factors
    • different symptoms / progression
    • different age-onsets.
  • This suggests that effective treatments need to be tailored to the subtype.

A two-year study which involved metabolic testing of 50 people, suggests that Alzheimer's disease consists of three distinct subtypes, each one of which may need to be treated differently. The finding may help explain why it has been so hard to find effective treatments for the disease.

The subtypes are:

  • Inflammatory, in which markers such as C-reactive protein and serum albumin to globulin ratios are increased.
  • Non-inflammatory, in which these markers are not increased but other metabolic abnormalities (such as insulin resistance, hypovitaminosis D, and hyper-homocysteinemia) are present. This tends to affect slightly older individuals than the first subtype: 80s rather than 70s.
  • Cortical, which affects relatively young individuals (typically 50s- early 70s) and appears more widely distributed across the brain than the other subtypes, showing widespread cortical atrophy rather than marked hippocampal atrophy. It typically presents with language and number difficulties first, rather than memory loss. Typically, there is an impaired ability to hold onto a train of thought. It is often misdiagnosed, typically affects people without a family history of Alzheimer's, who do not have an Alzheimer's-related gene, and is associated with a significant zinc deficiency (Zinc is implicated in multiple Alzheimer's-related metabolic processes, such as insulin resistance, chronic inflammation, ADAM10 proteolytic activity, and hormonal signaling. Zinc deficiency is relatively common, and associated with increasing age.).

The cortical subtype appears to be fundamentally a different condition than the other two.

I note a study I reported on last year, that found different molecular structures of amyloid-beta fibrils in the brains of Alzheimer's patients with different clinical histories and degrees of brain damage. That was a very small study, indicative only. However, I do wonder if there's any connection between these two findings. At the least, I think this approach a promising one.

The idea that there are different types of Alzheimer's disease is of course consistent with the research showing a variety of genetic risk factors, and an earlier study indicating at least two pathways to Alzheimer's.

It's also worth noting that the present study built on an earlier study, which showed that a program of lifestyle, exercise and diet changes designed to improve the body's metabolism reversed cognitive decline within 3-6 months in nine out of 10 patients with early Alzheimer's disease or its precursors. Note that this was a very small pilot program, and needs a proper clinical trial. Nevertheless, it is certainly very interesting.

http://www.eurekalert.org/pub_releases/2015-09/uoc--adc091615.php

Reference: 

Bredesen, D.E. 2015. Metabolic profiling distinguishes three subtypes of Alzheimer's disease. AGING, 7 (8), 595-600. Full text at http://www.impactaging.com/papers/v7/n8/full/100801.html

Bredesen, D.E. 2014. Reversal of cognitive decline: A novel therapeutic program. AGING, Vol 6, No 9 , pp 707-717. Full text at http://www.impactaging.com/papers/v6/n9/full/100690.html

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Diabetes and tau tangles linked independently of Alzheimer's

  • Type 2 diabetes is known to increase the risk of Alzheimer's disease.
  • In a reasonably large study, diabetes was found to be linked with higher levels of tau protein, regardless of the presence of dementia.
  • Diabetes was also linked with greater brain shrinkage.
  • The finding adds to evidence that diabetes increases the risk of cognitive impairment in old age.

A study involving older adults has found that diabetes was associated with higher levels of tau protein and greater brain atrophy.

The study involved 816 older adults (average age 74), of whom 397 had mild cognitive impairment, 191 had Alzheimer's disease, and 228 people had no cognitive problems. Fifteen percent (124) had diabetes.

Those with diabetes had greater levels of tau protein in the spinal and brain fluid regardless of cognitive status. Tau tangles are characteristic of Alzheimer's.

Those with diabetes also had cortical tissue that was an average of 0.03 millimeter less than those who didn't have diabetes, regardless of their cognitive status. This greater brain atrophy in the frontal and parietal cortices may be partly related to the increase in tau protein.

There was no link between diabetes and amyloid-beta, the other main pathological characteristic of Alzheimer's.

Previous research has indicated that people with type 2 diabetes have double the risk of developing dementia. Previous research has also found that those who had been diabetic for longer had a greater degree of brain atrophy

The findings support the idea that type 2 diabetes may have a negative effect on cognition independent of dementia, and that this effect may be driven by an increase in tau phosphorylation.

http://www.eurekalert.org/pub_releases/2015-09/aaon-dab082715.php

Reference: 

[3990] Moran, C., Beare R., Phan T. G., Bruce D. G., Callisaya M. L., Srikanth V., et al.
(2015).  Type 2 diabetes mellitus and biomarkers of neurodegeneration.
Neurology. 10.1212/WNL.0000000000001982.

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Mental imagery training improves multiple sclerosis patients' cognition

  • Difficulties in remembering past events and imagining future ones are often experienced by those with multiple sclerosis.
  • A trial involving patients with MS has found that training in mentally visualizing imaginery scenarios can improve their ability to recall past events.
  • Deficits in event memory and imagination have also been found in older adults, so this finding might have wider application.

Training in a mental imagery technique has been found to help multiple sclerosis patients in two memory domains often affected by the disease: autobiographical memory and episodic future thinking.

The study involved 40 patients with relapsing-remitting MS, all of whom were receiving regular drug therapy and all of whom had significant brain atrophy. Participants were randomly assigned to one of three groups, one of which received the imagery training (17 participants), while the other two were controls — a control receiving a sham verbal training (10) and a control receiving no training (13). The six training sessions lasted two hours and occurred once or twice a week.

The training involved:

  • mental visualization exercises of increasing difficulty, using 10 items that the patient had to imagine and describe, looking at both static aspects (such as color and shape) and an action carried out with the item
  • guided construction exercises, using 5 scenarios involving several characters (so, for example, the patient might start with the general idea of a cook preparing a meal, and be guided through more complexities, such as the type of table, the ingredients being used, etc)
  • self-visualization exercises, in which the patient imagined themselves within a scenario.

Autobiographical memory and episodic future thinking were assessed, before and after, using an adapted version of the Autobiographical Interview, which involves subjects recalling events from earlier periods in their life, in response to specific cue words. The events are supposed to be unique, and the subjects are asked to recall as many details as possible.

Only those receiving the training showed a significant improvement in their scores.

Those who had the imagery training also reported an increase in general self-confidence, with higher levels of control and vitality.

Remembering past events and imagining future ones are crucial cognitive abilities, with more far-reaching impacts than may be immediately obvious. For example, episodic future thought is important for forming and carrying out intentions.

These are also areas which may be affected by age. A recent study, for example, found that older adults are less likely to spontaneously acquire items that would later allow a problem to be solved, and are also less likely to subsequently use these items to solve the problems. An earlier study found that older adults have more difficulty in imagining future experiences.

These results, then, that show us that people with deficits in specific memory domains can be helped by specific training, is not only of interest to those with MS, but also more generally.

http://www.eurekalert.org/pub_releases/2015-08/ip-mvi082515.php

Reference: 

[3984] Ernst, A., Blanc F., De Seze J., & Manning L.
(2015).  Using mental visual imagery to improve autobiographical memory and episodic future thinking in relapsing-remitting multiple sclerosis patients: A randomised-controlled trial study.
Restorative Neurology and Neuroscience. Preprint(Preprint), 1 - 18.

[3986] Lyons, A. D., Henry J. D., Rendell P. G., Corballis M. C., & Suddendorf T.
(2014).  Episodic foresight and aging..
Psychology and Aging. 29(4), 873 - 884.

[3987] Rendell, P. G., Bailey P. E., Henry J. D., Phillips L. H., Gaskin S., & Kliegel M.
(2012).  Older adults have greater difficulty imagining future rather than atemporal experiences..
Psychology and Aging. 27(4), 1089 - 1098.

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Coping with cognitive decline in MS

Cognitive impairment affects 40-65% of people with MS. Why? In the past year, a number of studies have helped us build a better picture of the precise nature of cognitive problems that may affect multiple sclerosis sufferers:

  • poorer performance on executive function tasks is fully explained by slower processing speed (which is presumably a function of the degradation in white matter characteristic of MS)
  • slowing in processing speed is associated with weaker connections between the executive area and the brain regions involved in carrying out cognitive tasks
  • cognitive reserve helps counter the decline in memory and cognitive efficiency
  • brain reserve (greater brain volume, ie less shrinkage) helps counter the decline in cognitive efficiency
  • working memory capacity explains the link between cognitive reserve and long-term memory
  • subjective cognitive fatigue is linked to the time spent on the task, not on its difficulty
  • mnemonic training helps protect against cognitive decline, but appears to be less helpful in those with slow processing speed.

What all this implies is that a multi-pronged approach is called for, involving:

  • working memory training
  • training in effective memory strategies
  • practice in breaking down cognitive tasks into more manageable chunks of time
  • practice in framing tasks to accommodate slower processing speed
  • physical and mental activities that encourage neurogenesis (growing more neurons) and synaptogenesis (growing more connections).

Here's some more detail on those studies:

Slow processing speed accounts for executive deficits in MS

A study of 50 patients with MS and 28 healthy controls found no differences in performance on executive function tasks when differences in processing speed were controlled for. In other words, although MS patients performed more poorly than controls on these tasks, the difference was fully accounted for by the differences in processing speed. There were no differences in performance when there was no processing speed component to the task. Similarly, MS patients with a greater degree of brain atrophy performed more poorly than those with less atrophy, but again, this only occurred when there was a processing speed aspect to the task, and was fully accounted for by processing speed differences.

http://www.eurekalert.org/pub_releases/2014-09/kf-kfs091614.php

[3939] Leavitt, V. M., Wylie G., Krch D., Chiaravalloti N. D., DeLuca J., & Sumowski J. F.
(2014).  Does slowed processing speed account for executive deficits in multiple sclerosis? Evidence from neuropsychological performance and structural neuroimaging..
Rehabilitation Psychology. 59(4), 422 - 428.

Functional connectivity factor in cognitive decline in MS

A brain imaging study involving 29 participants with relapsing-remitting MS and 23 age- and sex- matched healthy controls found that, as expected, those with MS were much slower on a processing speed task, although they were as accurate as the controls. This slowing was associated with weaker functional connections between the dorsolateral prefrontal cortex (the executive area) and the regions responsible for carrying out the task. It's thought that this is probably due to decreased white matter (white matter degradation is symptomatic of MS).

http://www.eurekalert.org/pub_releases/2015-07/cfb-srb070715.php

[3938] Hubbard, N. A., Hutchison J. L., Turner M. P., Sundaram S., Oasay L., Robinson D., et al.
(2015).  Asynchrony in Executive Networks Predicts Cognitive Slowing in Multiple Sclerosis.
Neuropsychology.

Brain and cognitive reserve protect against cognitive decline in MS

A study compared memory, cognitive efficiency, vocabulary, and brain volume in 40 patients with MS, at baseline and 4.5 years later. After controlling for disease progression, they found that those with better vocabulary (a proxy for cognitive reserve) experienced less decline in memory and cognitive efficiency, and those with less brain atrophy over the period showed less decline in cognitive efficiency.

Cognitive efficiency is a somewhat fuzzy concept, but essentially has to do with how much time and effort you need to acquire new knowledge; in this study, it was assessed using the Symbol Digit Modalities Test and Paced Auditory Serial Addition Task, two tests commonly used to detect cognitive impairment in MS patients.

http://www.eurekalert.org/pub_releases/2014-04/kf-mrf043014.php

[3943] Sumowski, J. F., Rocca M. A., Leavitt V. M., Dackovic J., Mesaros S., Drulovic J., et al.
(2014).  Brain reserve and cognitive reserve protect against cognitive decline over 4.5 years in MS.
Neurology. 82(20), 1776 - 1783.

Working memory capacity accounts for link between cognitive reserve & better memory

A study involving 70 patients with MS has found that working memory capacity explained the relationship between cognitive reserve and long-term memory, suggesting that interventions targeted at working memory may help protect against decline in long-term memory.

http://www.eurekalert.org/pub_releases/2014-09/kf-kfm090914.php

[3941] Sandry, J., & Sumowski J. F.
(2014).  Working Memory Mediates the Relationship between Intellectual Enrichment and Long-Term Memory in Multiple Sclerosis: An Exploratory Analysis of Cognitive Reserve.
Journal of the International Neuropsychological Society. 20(08), 868 - 872.

Cognitive fatigue linked to time on task, not difficulty

A study investigating cognitive fatigue in 32 individuals with MS and 24 controls has found that subjective and objective fatigue were independent of one another, and that subjective cognitive fatigue increased as time on task increased. This increase in cognitive fatigue was greater in the MS group. No relationship was found between cognitive fatigue and cognitive load. Fatigue was greater for the processing speed task than the working memory task.

In other words, the length of time spent is far more important than the difficulty of the task.

http://www.eurekalert.org/pub_releases/2015-01/kf-kfr012115.php

[3940] Sandry, J., Genova H. M., Dobryakova E., DeLuca J., & Wylie G.
(2014).  Subjective cognitive fatigue in multiple sclerosis depends on task length.
Frontiers in Neurology. 5, 214.

Story mnemonic training helps some

A series of small studies have found cognitive benefits for MS patients from a 10-session training program designed to build their memory skills using a modified story mnemonic. The MEMREHAB Trial involved 85 patients with MS, of whom 45 received the training. In the most recent analyses of the data, the benefits were found to be maintained six months later, but unfortunately, it appears that those with processing speed deficits gain less benefit from the training.

The training consists of four 45-minute sessions focused on building imagery skills, in which participants were given a story with highly visualizable scenes and given facilitated practice in using visualization to help them remember the story. In the next four sessions, they were given lists of words and instructed in how to build a memorable story from these words, that they could visualize. The sessions employed increasingly unrelated word lists. In the final two sessions, participants were taught how to apply the technique in real-world situations.

http://www.eurekalert.org/pub_releases/2014-08/kf-kfs080814.php

[3936] Chiaravalloti, N. D., & DeLuca J.
(2015).  The influence of cognitive dysfunction on benefit from learning and memory rehabilitation in MS: A sub-analysis of the MEMREHAB trial.
Multiple Sclerosis (Houndmills, Basingstoke, England).

[3937] Dobryakova, E., Wylie G. R., DeLuca J., & Chiaravalloti N. D.
(2014).  A pilot study examining functional brain activity 6 months after memory retraining in MS: the MEMREHAB trial.
Brain Imaging and Behavior. 8(3), 403 - 406.

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Diabetes & cognitive impairment

A review and a large study have recently added to the growing evidence that type 2 diabetes is not only a risk factor for Alzheimer's, but is also linked to poorer cognitive function and faster age-related cognitive decline. The amount of this also seems to be related to glucose control in a dose-dependent manner.

Somewhat surprisingly, there is evidence that the association is not linked to vascular factors, but is in significant part explained by neuron loss. That part is not surprising — brains 'naturally' shrink with age, and growing evidence points to the importance of exercise (which promotes the growth of new neurons) in combating that loss. If diabetics are less likely to exercise (which seems likely, given the strong association with obesity), this may, at least in part, account for the greater brain atrophy.

Type 2 diabetes linked to poorer executive function

A meta-analysis of 60 studies involving a total of 9815 people with Type 2 diabetes and 69,254 control individuals, has found a small but reliable association between diabetes and poorer executive function. This was true across all aspects of executive function tested: verbal fluency, mental flexibility, inhibition, working memory, and attention.

Unfortunately, effective diabetes management does depend quite heavily on executive function, making this something of a negative feedback cycle.

http://www.eurekalert.org/pub_releases/2015-02/uow-t2d021315.php

Diabetes in midlife linked to greater age-related cognitive decline

A long-running U.S. study involving 13,351 adults, has found that cognitive decline over 19 years was 19% greater among those who had diabetes in midlife. Moreover, cognitive decline increased with higher hemoglobin A1c level and longer duration of diabetes.

At the beginning of the study, participants were aged 48-67 (median: 57), and 13% of participants were diagnosed as diabetic. Cognition was tested using delayed word recall, digit symbol substitution, and word fluency tests.

The findings support the view that glucose control in midlife is important to protect against cognitive decline later in life.

http://www.jwatch.org/na36497/2014/12/31/diabetes-midlife-associated-with-accelerated-cognitive

http://www.sciencedaily.com/releases/2014/12/141201191253.htm

http://www.psychiatryadvisor.com/diabetes-may-accelerate-cognitive-decline/article/386208/

Brain atrophy linked with cognitive decline in diabetes

A 2013 study showed that almost half of the cognitive impairment seen among diabetics was explained by their loss of gray matter.

Brain scans and cognitive tests of 350 people with Type 2 diabetes and 363 people without diabetes revealed that those with diabetes had more cerebral infarcts and greater shrinkage in specific regions of the brain. Diabetes was associated with poorer visuospatial memory, planning, visual memory, and processing speed. These associations were independent of vascular risk factors, cerebrovascular lesions, or white matter volume, but almost half of the associations were explained by the shrinkage of gray matter in the hippocampus and across the brain.

http://www.eurekalert.org/pub_releases/2013-09/mu-bal091113.php

Reference: 

Vincent, C. & Hall, P.A. 2015. Executive Function in Adults With Type 2 Diabetes: A Meta-Analytic Review. Psychosomatic Medicine, doi: 10.1097/PSY.0000000000000103

[3910] Rawlings, A. M., A. Sharrett R., Schneider A. L. C., Coresh J., Albert M., Couper D., et al.
(2014).  Diabetes in midlife and cognitive change over 20 years: a cohort study.
Annals of Internal Medicine. 161(11), 785 - 793.

[3909] Moran, C., Phan T. G., Chen J., Blizzard L., Beare R., Venn A., et al.
(2013).  Brain Atrophy in Type 2 Diabetes Regional distribution and influence on cognition.
Diabetes Care. 36(12), 4036 - 4042.

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