Health & age-related problems

Warmer weather hurts cognition in MS sufferers

A small study finds memory and processing speed tend to be significantly worse in warmer weather for those suffering from multiple sclerosis.

It’s estimated that 43%-70% of those with multiple sclerosis suffer from some level of cognitive impairment (yes, a very broad range! perhaps the finding of this study offers one clue why). Most commonly, this is seen in slower processing speed, impaired memory, impaired executive function, and poorer visuospatial processing. There are a number of factors that have been implicated in why some people suffer from cognitive impairment and others don’t, such as age of onset and male gender. As with dementia, depression also may be a factor, while cognitive reserve appears protective.

Another factor specific to MS may be temperature. Previous research has shown that people with MS tend to have more symptoms and greater lesion activity when the weather is warmer. More recently, this association has also been found with memory and processing speed.

I mentioned this research very briefly last year, when it was presented at conference. Here are a few more details now the journal article is out.

There were two parts to this study: cross-sectional and longitudinal. In the former, 40 patients with MS and 40 healthy controls were recruited throughout the calendar year, and cognitive performance and outdoor temperature were recorded for the day of testing. A different group of 45 patients with MS were recruited for the longitudinal analysis, in which cognitive status and outdoor temperature were recorded twice, six months apart.

In the cross-sectional analysis, warmer temperature was related to significantly worse cognitive performance in patients with MS, while controls were unaffected by temperature. Similarly, the longitudinal analysis found that an increased outdoor temperature from the first cognitive test to the second was related to a decline in cognitive performance within patients with MS.

Long-term cognitive effects of breast cancer chemotherapy

A study has found greater cognitive decline in older women who were given chemotherapy for breast cancer 20 years ago.

Women who received a once-standard type of chemotherapy regimen for breast cancer between 1976 and 1995 have been found to score worse on cognitive tests than women who never had cancer. Specifically, they tended to have lower scores on tests of immediate and delayed verbal memory, executive function, information processing speed, and psychomotor speed. The difference was comparable to some six years of age-related decline.

CMF chemotherapy was the standard of care for breast cancer worldwide from the 1970s through the 1990s. Some of the chemicals (shown to be associated with impaired learning and memory in animal studies) are still commonly incorporated in modern chemotherapeutic regimens for breast cancer.

The study compared the performance of 196 women who had received CMF chemotherapy to that of 1,509 women enrolled in the Rotterdam Study. All participants were aged 50-80 at the beginning of the study. Factors such as age, education, and depression score were taken into account in the analysis.

For more about the effects of chemotherapy on cognition

Larger belly linked to memory problems in people with HIV

HIV-related cognitive impairment is significantly associated with a greater waist circumference, and in older adults, with diabetes.

A study involving 130 HIV-positive people has found that memory impairment was associated with a significantly larger waistline.

Some 40% of participants (average age 46) had impaired cognition. This group had an average waist circumference of 39 inches, compared to 35 inches for those without such problems. Memory impairment was also linked to diabetes in those older than 55 (15% of those with memory problems had diabetes compared to only 3% of those without memory problems).

Waistline was more important than BMI. Unfortunately, some anti-HIV drugs cause weight gain in this area.

The finding is consistent with evidence that abdominal weight is more important than overall weight for cognitive impairment and dementia in the general population.

For more about HIV-related cognitive impairment

Prevalence of cognitive problems among older adults

A large Swedish twin study reveals the prevalence of age-related cognitive impairment and points to the greater importance of environment over genes. Another very large study points to marked regional variation in mild cognitive impairment.

Data from 11,926 older twins (aged 65+) has found measurable cognitive impairment in 25% of them and subjective cognitive impairment in a further 39%, meaning that 64% of these older adults were experiencing some sort of cognitive impairment.

Although subjective impairment is not of sufficient magnitude to register on our measurement tools, that doesn’t mean that people’s memory complaints should be dismissed. It is likely, given the relative crudity of standard tests, that people are going to be aware of cognitive problems before they grow large enough to be measurable. Moreover, when individuals are of high intelligence or well-educated, standard tests can be insufficiently demanding. [Basically, subjective impairment can be thought of as a step before objective impairment, which itself is a step before mild cognitive impairment (MCI is a formal diagnosis, not simply a descriptive title), the precursor to Alzheimer’s. Note that I am calling these “steps” as a way of describing a continuum, not an inevitable process. None of these steps means that you will inevitably pass to the next step, but each later step will be preceded by the earlier steps.]

Those with subjective complaints were younger, more educated, more likely to be married, and to have higher socio-economic status, compared to those with objective impairment — supporting the idea that these factors provide some protection against cognitive decline.

The use of twins reveals that environment is more important than genes in determining whether you develop cognitive impairment in old age. For objective cognitive impairment, identical twins had a concordance rate of 52% compared to 50% in non-identical same-sex twins and 29% in non-identical different-gender twins. For subjective impairment, the rates were 63%, 63%, and 42%, respectively.

National variation in MCI prevalence

Another very large study, involving 15,376 older adults (65+), has explored the prevalence of amnestic MCI in low- and middle-income countries: Cuba, Dominican Republic, Peru, Mexico, Venezuela, Puerto Rico, China, and India. Differences between countries were marked, with only 0.6% of older adults in China having MCI compared to 4.6% in India (Cuba 1.5%, Dominican Republic 1.3%, Peru 2.6%, Mexico 2.8%, Venezuela 1%, Puerto Rico 3% — note that I have selected the numbers after they were standardized for age, gender, and education, but the raw numbers are not greatly different).

Studies to date have focused mainly on European and North American populations, and have provided prevalence estimates ranging from 2.1%-11.5%, generally hovering around 3-5% (for example, Finland 5.3%, Italy 4.9%, Japan 4.9%, the US 6% — but note South Korea 9.7% and Malaysia 15.4%).

What is clear is that there is considerable regional variation.

Interestingly, considering their importance in Western countries, the effects of both age and education on prevalence of aMCI were negligible. Granted that age and education norms were used in the diagnosis, this is still curious. It may be that there was less variance in educational level in these populations. Socioeconomic status was, however, a factor.

Participants were also tested on the 12-item WHO disability assessment schedule (WHODAS-12), which assesses five activity-limitation domains (communication, physical mobility, self-care, interpersonal interaction, life activities and social participation). MCI was found to be significantly associated with disability in Peru, India, and the Dominican Republic (but negatively associated in China). Depression (informant-rated) was also only associated with MCI in some countries.

All of this, I feel, emphasizes the situational variables that determine whether an individual will develop cognitive impairment.

Reference: 

Caracciolo B, Gatz M, Xu W, Pedersen NL, Fratiglioni L. 2012. Differential Distribution of Subjective and Objective Cognitive Impairment in the Population: A Nation-Wide Twin-Study. Journal of Alzheimer's Disease, 29(2), 393-403.

[2801] Sosa, A. L., Albanese E., Stephan B. C. M., Dewey M., Acosta D., Ferri C. P., et al. (2012).  Prevalence, Distribution, and Impact of Mild Cognitive Impairment in Latin America, China, and India: A 10/66 Population-Based Study. PLoS Med. 9(2), e1001170 - e1001170.

Full text available at http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed....

Severe, rapid memory loss linked to future, fatal strokes

A large, long-running study has revealed that older adults who suffered a fatal stroke showed significantly faster cognitive decline in the years preceding the stroke compared to stroke survivors and stroke-free adults.

A ten-year study following 12,412 middle-aged and older adults (50+) has found that those who died after stroke had more severe memory loss in the years before stroke compared to those who survived stroke and those who didn't have a stroke.

Participants were tested every two years, using a standard word-recall list to measure memory loss (or caregiver assessment for those whose memory loss was too severe). During the decade of the study, 1,027 participants (8.3%) survived a stroke, 499 (4%) died after stroke, and 10,886 (87.7%) remained stroke-free over the study period.

Before having a stroke, those who later survived a stroke had worse average memory than similar individuals who never had a stroke, however their rate of memory decline was similar (0.034 and 0.028 points per year, respectively). Those who later died after a stroke, on the other hand, showed significantly faster memory decline (0.118 points per year).

Whether this is because those who die after stroke have a more compromised brain prior to the stroke, or because greater memory impairment makes people more vulnerable in the wake of a stroke, cannot be told from this data (and indeed, both factors may be involved).

Among survivors, stroke had a significant effect on memory decline, with memory scores dropping an average of 0.157 points at the time of the stroke — an amount equivalent to around 5.6 years of memory decline in similarly-aged stroke-free adults. However, in subsequent years, decline was only a little greater than it had been prior to the stroke (0.038 points per year).

(You can see a nice graph of these points here.)

Reference: 

Wang, Q., Capistrant, B.D., Ehntholt, A. & Glymour, M.M. 2012. Abstract 31: Rate of Change in Memory Functioning Before and After Stroke Onset. Presented at the American Stroke Association's International Stroke Conference 2012. http://stroke.ahajournals.org/cgi/content/meeting_abstract/43/2_MeetingAbstracts/A31?sid=960f2015-06d1-478f-8c03-c00994d35f2c

Identifying those with cognitive impairment

A brief questionnaire designed to identify those with Alzheimer’s has been found to be useful in also identifying those with MCI. A large study confirms the value of such tools but also points to their limitations

New data from the ongoing validation study of the Alzheimer's Questionnaire (AQ), from 51 cognitively normal individuals (average age 78) and 47 aMCI individuals (average age 74), has found that the AQ is effective in identifying not only those with Alzheimer’s but also those older adults with mild cognitive impairment.

Of particular interest is that four questions were strong indicators of aMCI. These related to:

  • repeating questions and statements,
  • trouble knowing the date or time,
  • difficulties managing finances, and
  • decreased sense of direction.

The AQ consists of 21 yes/no questions designed to be answered by a relative or carer. The questions fall into five categories: memory, orientation, functional ability, visuospatial ability, and language. Six of these questions are known to be predictive of AD and are given extra weighting, resulting in a score out of 27. A score above 15 was indicative of AD, and between 5 and 14 of aMCI. Scores of 4 or lower indicate that the person does not have significant memory problems.

The questionnaire is not of course definitive, but is intended as an indicator for further testing. Note, too, that all participants in this study were Caucasian.

The value and limitations of brief cognitive screenings

The value of brief cognitive screenings combined with offering further evaluation is demonstrated in a recent large VA study, which found that, of 8,342 Veterans aged 70+ who were offered screening (the three-minute Mini-Cog), 8,063 (97%) accepted, 2,081 (26%) failed the screen, and 580 (28%) agreed to further evaluation. Among those accepting further evaluation, 93% were found to have cognitive impairment, including 75% with dementia.

Among those who declined further evaluation, 17% (259/1,501) were diagnosed with incident cognitive impairment through standard clinical care. In total, the use of brief cognitive screenings increased the numbers with cognitive impairment to 11% (902/8,063) versus 4% (1,242/28,349) in similar clinics without this program.

Importantly, the limits of such questionnaires were also demonstrated: 118 patients who passed the initial screen nevertheless requested further evaluation, and 87% were found to have cognitive impairment, including 70% with dementia.

This should not be taken as a reason not to employ such cognitive tests! There are two points that should, I think, be taken from this:

  • Routine screening of older adults is undoubtedly an effective strategy for identifying those with cognitive impairment.
  • Individuals who pass such tests but nevertheless believe they have cognitive problems should be taken seriously.

Why diabetes is linked to cognitive impairment in older adults

The link between diabetes and cognitive impairment in older adults seems to be mediated by the release of molecules that increase inflammation, leading to constricted blood vessels, thus reduced blood flow, and finally loss of gray matter.

Why is diabetes associated with cognitive impairment and even dementia in older adults? New research pinpoints two molecules that trigger a cascade of events that end in poor blood flow and brain atrophy.

The study involved 147 older adults (average age 65), of whom 71 had type 2 diabetes and had been taking medication to manage it for at least five years. Brain scans showed that the diabetic patients had greater blood vessel constriction than the age- and sex-matched controls, and more brain atrophy. The reduction in brain tissue was most marked in the grey matter in the parietal and occipital lobes and cerebellum. Research has found that, at this age, while the average brain shrinks by about 1% annually, a diabetic brain might shrink by as much as 15%. Diabetics also had more white matter hyperintensities in the temporal, parietal and occipital lobes.

Behaviorally, the diabetics also had greater depression, slower walking, and executive dysfunction.

The reduced performance of blood vessels (greater vasoconstriction, blunted vasodilatation), and increased brain atrophy in the frontal, temporal, and parietal lobes, was associated with two adhesion molecules – sVCAM and sICAM. White matter hyperintensities were not associated with the adhesion molecules, inflammatory markers, or blood vessel changes.

It seems that the release of these molecules, probably brought about by chronic hyperglycemia and insulin resistance, produces chronic inflammation, which in turn brings about constricted blood vessels, reduced blood flow, and finally loss of neurons. The blood vessel constriction and the brain atrophy were also linked to higher glucose levels.

The findings suggest that these adhesion molecules provide two biomarkers of vascular health that could enable clinicians to recognize impending brain damage, that could then perhaps be prevented.

The findings also add weight to the growing evidence that diabetes management is crucial in preventing cognitive decline.

Reference: 

Abnormal brain blood flow persisting in some Gulf War veterans

In a small study, some Gulf War syndromes are shown to have effects on the hippocampus that have persisted for 20 years, and in some cases worsened.

So-called ‘Gulf War syndrome’ is a poorly understood chronic condition associated with exposure to neurotoxic chemicals and nerve gas, and despite its name is associated with three main syndromes: impaired cognition (syndrome 1); confusion-ataxia (syndrome 2); central neuropathic pain (syndrome 3). Those with syndrome 2 are the most severely affected. Note that the use of the term ‘impaired cognition’ for syndrome 1 is not meant to indicate that the other syndromes show no impaired cognition; rather, it signals the absence of other primary symptoms such as ataxia and pain.

Symptoms of Gulf War syndrome include fatigue, neuropathic pain, memory and concentration deficits, balance disturbances and depression. Many of these symptoms suggest impairment of the hippocampus (among other regions, in particular the basal ganglia).

The new study follows up on an earlier study, with many of the same participants involved. A new, more sensitive, technique for assessing blood flow in the hippocampus was used to assess 35 patients with Gulf War syndromes and 13 controls. In the study of eleven years previous, those with syndrome 1 (impaired cognition) showed similar responses as the controls, while those with syndrome 2 (confusion-ataxia) showed abnormal blood flow in the right hippocampus.

In the present study, that abnormal hippocampal blood flow had progressed to the left hippocampus for those with syndrome 2 and to both hippocampi for those with syndrome 3. The results indicate that this alteration of hippocampal blood flow persists and can even worsen.

Around a quarter of U.S. military personnel deployed to the 1991 Persian Gulf War are estimated to be affected by Gulf War syndrome. Previous research has suggested genetic variation may underlie individuals’ vulnerability to neurotoxins.

What transient amnesia tells us about autobiographical memory and brain plasticity

Brain scans of those suffering from transient global amnesia indicate a permanent role of the hippocampus in autobiographical memory, and demonstrate the brain’s ability to self-repair.

When a middle-aged woman loses her memory after sex, it naturally makes the headlines. Many might equate this sort of headline to “Man marries alien”, but this is an example of a rare condition — temporary, you will be relieved to hear — known as transient global amnesia. Such abrupt, localized loss of autobiographical memory is usually preceded by strenuous physical activity or stressful events. It generally occurs in middle-aged or older adults, but has been known to occur in younger people. In those cases, there may be a history of migraine or head trauma.

Following an earlier study in which 29 of 41 TGA patients were found to have small lesions in the CA1 region of the hippocampus, scanning of another 16 TGA patients has revealed 14 had these same lesions. It seems likely that all the patients had such lesions, but because they are very small and don’t last long, they’re easy to miss. The lesion is best seen after 24-72 hours, but is gone after 5-6 days.

At the start of one of these attacks, memory for the first 30 years of life was significantly impaired, but still much better than memory for the years after that. There was a clear temporal gradient, with memory increasingly worse for events closer in time. There was no difference between events in the previous year and events in the previous five years, but a clear jump at that five-year point.

The exact location of the lesions was significant: when the lesion was in the anterior part of the region, memory for recent events was more impaired.

The hippocampus is known to be crucially involved in episodic memory (memory for events), and an integral part of the network for autobiographical memory. In recent years, it has come to be thought that such memories are only hosted temporarily by the hippocampus, and over a few years come to be permanently lodged in the neocortex (the standard consolidation model). Evidence from a number of studies of this change at the five-year mark has been taken as support for this theory. According to this, then, older memories should be safe from hippocampal damage.

An opposing theory, however, is that the hippocampus continues to be involved in such memories, with both the neocortex and the hippocampus involved in putting together reconsolidated memories (the multiple trace model). According to this model, each retrieval of an episodic memory creates a new version in the hippocampus. The more versions, the better protected a memory will be from any damage to the hippocampus.

The findings from this study show that while there is indeed a significant difference between older and more recent memories, the CA1 region of the hippocampus continues to be crucial for retrieving older memories, and for our sense of self-continuity.

Interestingly, some studies have also found a difference between the left and right hemispheres, with the right hippocampus showing a temporal gradient and the left hippocampus showing constant activation across all time periods. Such a hemisphere difference was not found in the present study. The researchers suggest that the reason may lie in the age of the participants (average age was 68), reflecting a reduction in hemispheric asymmetry with age.

There’s another message in this study. In these cases of TGA, memory function is restored within 24 hours (and generally sooner, within 6-10 hours). This shows how fast the brain can repair damage. Similarly, the fact that such tiny lesions have temporary effects so much more dramatic than the more lasting effects of larger lesions, is also a tribute to the plasticity of the brain.

The findings are consistent with findings of a preferential degeneration of CA1 neurons in the early stages of Alzheimer's disease, and suggest a target for treatment.

Reference: 

Timing of estrogen therapy is crucial

A rat study provides further evidence that the conflicting findings on the benefit of estrogen therapy stem from the importance of timing.

The very large and long-running Women's Health Initiative study surprised everyone when it produced its finding that hormone therapy generally increased rather than decreased stroke risk as well as other health problems. But one explanation for that finding might be that many of the women only received hormone replacement therapy years after menopause. There are indications that timing is crucial.

This new rat study involved female rats equivalent to human 60-65 year olds, about a decade past menopause.  An enzyme called CHIP (carboxyl terminus of Hsc70 interacting protein) was found to increase binding with estrogen receptors, resulting in about half the receptors getting hauled to the cell's proteosome to be chopped up and degraded. When some of the aged rats were later treated with estrogen, mortality increased. When middle-aged rats were treated with estrogen, on the other hand, results were positive.

In other words, putting in extra estrogen after the number of estrogen receptors in the brain has been dramatically decreased is a bad idea.

While this study focused on mortality, other research has produced similar conflicting results as to whether estrogen therapy helps fight age-related cognitive impairment in women (see my report). It’s interesting to note that this effect only occurred in the hippocampus — estrogen receptors in the uterus were unaffected.

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