neurogenesis

Nutrient cocktail for early Alzheimer's passes second trial

September, 2012

A second controlled trial of the nutrient cocktail Souvenaid has confirmed its cognitive benefits for those in the early stages of Alzheimer’s.

Two years ago, I reported on a clinical trial of a nutrient cocktail called Souvenaid for those with early Alzheimer’s. The three-month trial, involving 225 patients, had some success in improving verbal recall, with those with the mildest level of impairment benefiting the most.

The ‘cocktail’, designed by a MIT professor of brain and cognitive science, includes choline, uridine and the omega-3 fatty acid DHA. Earlier research indicated that these nutrients — precursors to the lipid molecules that help make up neural membranes — need to be administered together to be effective. In animal studies, the cocktail increased the number of dendritic spines, which are reduced in Alzheimer’s disease.

A further trial of the supplement has now been reported on. This randomized, controlled double-blind study followed 259 patients with early Alzheimer’s for six months. The placebo group was given an iso-caloric control product. Compliance was high (around 97%), and no serious side effects occurred.

During the first three months, all patients improved their verbal memory performance, but after that those on placebo began to deteriorate, while those on Souvenaid continued to improve. Their performance at the end of the trial was significantly better than that of the placebo group. Moreover, brain scans showed that their brains began to show more normal activity patterns, consistent with the regaining of greater synaptic function.

Because the supplement only seems to be effective for those in the early stages (in this study, participants averaged around 25 on a scale of dementia that ranges from 1 to 30, with 30 being normal), a two-year trial is now underway with patients with MCI.

Reference: 

Scheltens, P. et al. 2012. Efficacy of Souvenaid in Mild Alzheimer’s Disease: Results from a Randomized, Controlled Trial. Journal of Alzheimer’s Disease, 31 (1), 225-36.

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C-sections don’t trigger key protein in brain

September, 2012

A mouse study finds that a vital protein is triggered by natural birth, and its reduction in those delivered by C-section correlates with poorer memory and greater anxiety in adulthood.

In the light of a general increase in caesarean sections, it’s somewhat alarming to read about a mouse study that found that vaginal birth triggers the expression of a protein in the brains of newborns that improves brain development, and this protein expression is impaired in the brains of those delivered by C-section.

The protein in question —mitochondrial uncoupling protein 2 (UCP2) — is important for the development of neurons and circuits in the hippocampus. Indeed, it has a wide role, being involved in regulation of fuel utilization, mitochondrial bioenergetics, cell proliferation, neuroprotection and synaptogenesis. UCP2 is induced by cellular stress.

Among the mice, natural birth triggered UCP2 expression in the hippocampus (presumably because of the stress of the birth), which was reduced in those who were born by C-section. Not only were levels of UCP2 lower in C-section newborns, they continued to be lower through to adulthood.

Cell cultures revealed that inhibiting UCP2 led to decreased number of neurons, neuron size, number of dendrites, and number of presynaptic clusters. Mice with (chemically or genetically) inhibited UCP2 also showed behavioral differences indicative of greater levels of anxiety. They explored less, and they showed poorer spatial memory.

The effects of reduced UCP2 on neural growth means that factors that encourage the growth of new synapses, such as physical exercise, are likely to be much less useful (if useful at all). Could this explain why exercise seems to have no cognitive benefits for a small minority? (I’m speculating here.)

Although the researchers don’t touch on this (naturally enough, since this was a laboratory study), I would also speculate that, if the crucial factor is stress during the birth, this finding applies only to planned C-sections, not to those which become necessary during the course of labor.

UCP2 is also a critical factor in fatty acid utilization, which has a flow-on effect for the creation of new synapses. One important characteristic of breast milk is its high content of long chain fatty acids. It’s suggested that the triggering of UCP2 by natural birth may help the transition to breastfeeding. This in turn has its own benefits for brain development.

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How piano tuning changes the brain

September, 2012

In another example of how expertise in a specific area changes the brain, brain scans of piano tuners show which areas grow, and which shrink, with experience — and starting age.

I’ve reported before on how London taxi drivers increase the size of their posterior hippocampus by acquiring and practicing ‘the Knowledge’ (but perhaps at the expense of other functions). A new study in similar vein has looked at the effects of piano tuning expertise on the brain.

The study looked at the brains of 19 professional piano tuners (aged 25-78, average age 51.5 years; 3 female; 6 left-handed) and 19 age-matched controls. Piano tuning requires comparison of two notes that are close in pitch, meaning that the tuner has to accurately perceive the particular frequency difference. Exactly how that is achieved, in terms of brain function, has not been investigated until now.

The brain scans showed that piano tuners had increased grey matter in a number of brain regions. In some areas, the difference between tuners and controls was categorical — that is, tuners as a group showed increased gray matter in right hemisphere regions of the frontal operculum, the planum polare, superior frontal gyrus, and posterior cingulate gyrus, and reduced gray matter in the left hippocampus, parahippocampal gyrus, and superior temporal lobe. Differences in these areas didn’t vary systematically between individual tuners.

However, tuners also showed a marked increase in gray matter volume in several areas that was dose-dependent (that is, varied with years of tuning experience) — the anterior hippocampus, parahippocampal gyrus, right middle temporal and superior temporal gyrus, insula, precuneus, and inferior parietal lobe — as well as an increase in white matter in the posterior hippocampus.

These differences were not affected by actual chronological age, or, interestingly, level of musicality. However, they were affected by starting age, as well as years of tuning experience.

What these findings suggest is that achieving expertise in this area requires an initial development of active listening skills that is underpinned by categorical brain changes in the auditory cortex. These superior active listening skills then set the scene for the development of further skills that involve what the researchers call “expert navigation through a complex soundscape”. This process may, it seems, involve the encoding and consolidating of precise sound “templates” — hence the development of the hippocampal network, and hence the dependence on experience.

The hippocampus, apart from its general role in encoding and consolidating, has a special role in spatial navigation (as shown, for example, in the London cab driver studies, and the ‘parahippocampal place area’). The present findings extend that navigation in physical space to the more metaphoric one of relational organization in conceptual space.

The more general message from this study, of course, is confirmation for the role of expertise in developing specific brain regions, and a reminder that this comes at the expense of other regions. So choose your area of expertise wisely!

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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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Genes, brain size, brain atrophy, and Alzheimer’s risk

May, 2012

A round-up of genetic news. Several genes are linked to smaller brain size and faster brain atrophy in middle- & old age. The main Alzheimer's gene is implicated in leaky blood vessels, and shown to interact with brain size, white matter lesions, and dementia risk. Some evidence suggests early-onset Alzheimer's is not so dissimilar to late-onset Alzheimer's.

Genetic analysis of 9,232 older adults (average age 67; range 56-84) has implicated four genes in how fast your hippocampus shrinks with age (rs7294919 at 12q24, rs17178006 at 12q14, rs6741949 at 2q24, rs7852872 at 9p33). The first of these (implicated in cell death) showed a particularly strong link to a reduced hippocampus volume — with average consequence being a hippocampus of the same size as that of a person 4-5 years older.

Faster atrophy in this crucial brain region would increase people’s risk of Alzheimer’s and cognitive decline, by reducing their cognitive reserve. Reduced hippocampal volume is also associated with schizophrenia, major depression, and some forms of epilepsy.

In addition to cell death, the genes linked to this faster atrophy are involved in oxidative stress, ubiquitination, diabetes, embryonic development and neuronal migration.

A younger cohort, of 7,794 normal and cognitively compromised people with an average age of 40, showed that these suspect gene variants were also linked to smaller hippocampus volume in this age group. A third cohort, comprised of 1,563 primarily older people, showed a significant association between the ASTN2 variant (linked to neuronal migration) and faster memory loss.

In another analysis, researchers looked at intracranial volume and brain volume in 8,175 elderly. While they found no genetic associations for brain volume (although there was one suggestive association), they did discover that intracranial volume (the space occupied by the fully developed brain within the skull — this remains unchanged with age, reflecting brain size at full maturity) was significantly associated with two gene variants (at loci rs4273712, on chromosome 6q22, and rs9915547, on 17q21). These associations were replicated in a different sample of 1,752 older adults. One of these genes is already known to play a unique evolutionary role in human development.

A meta-analysis of seven genome-wide association studies, involving 10,768 infants (average age 14.5 months), found two loci robustly associated with head circumference in infancy (rs7980687 on chromosome 12q24 and rs1042725 on chromosome 12q15). These loci have previously been associated with adult height, but these effects on infant head circumference were largely independent of height. A third variant (rs11655470 on chromosome 17q21 — note that this is the same chromosome implicated in the study of older adults) showed suggestive evidence of association with head circumference; this chromosome has also been implicated in Parkinson's disease and other neurodegenerative diseases.

Previous research has found an association between head size in infancy and later development of Alzheimer’s. It has been thought that this may have to do with cognitive reserve.

Interestingly, the analyses also revealed that a variant in a gene called HMGA2 (rs10784502 on 12q14.3) affected intelligence as well as brain size.

Why ‘Alzheimer’s gene’ increases Alzheimer’s risk

Investigation into the so-called ‘Alzheimer’s gene’ ApoE4 (those who carry two copies of this variant have roughly eight to 10 times the risk of getting Alzheimer’s disease) has found that ApoE4 causes an increase in cyclophilin A, which in turn causes a breakdown of the cells lining the blood vessels. Blood vessels become leaky, making it more likely that toxic substances will leak into the brain.

The study found that mice carrying the ApoE4 gene had five times as much cyclophilin A as normal, in cells crucial to maintaining the integrity of the blood-brain barrier. Blocking the action of cyclophilin A brought blood flow back to normal and reduced the leakage of toxic substances by 80%.

The finding is in keeping with the idea that vascular problems are at the heart of Alzheimer’s disease — although it should not be assumed from that, that other problems (such as amyloid-beta plaques and tau tangles) are not also important. However, one thing that does seem clear now is that there is not one single pathway to Alzheimer’s. This research suggests a possible treatment approach for those carrying this risky gene variant.

Note also that this gene variant is not only associated with Alzheimer’s risk, but also Down’s syndrome dementia, poor outcome following TBI, and age-related cognitive decline.

On which note, I’d like to point out recent findings from the long-running Nurses' Health Study, involving 16,514 older women (70-81), that suggest that effects of postmenopausal hormone therapy for cognition may depend on apolipoprotein E (APOE) status, with the fastest rate of decline being observed among HT users who carried the APOe4 variant (in general HT was associated with poorer cognitive performance).

It’s also interesting to note another recent finding: that intracranial volume modifies the effect of apoE4 and white matter lesions on dementia risk. The study, involving 104 demented and 135 nondemented 85-year-olds, found that smaller intracranial volume increased the risk of dementia, Alzheimer's disease, and vascular dementia in participants with white matter lesions. However, white matter lesions were not associated with increased dementia risk in those with the largest intracranial volume. But intracranial volume did not modify dementia risk in those with the apoE4 gene.

More genes involved in Alzheimer’s

More genome-wide association studies of Alzheimer's disease have now identified variants in BIN1, CLU, CR1 and PICALM genes that increase Alzheimer’s risk, although it is not yet known how these gene variants affect risk (the present study ruled out effects on the two biomarkers, amyloid-beta 42 and phosphorylated tau).

Same genes linked to early- and late-onset Alzheimer's

Traditionally, we’ve made a distinction between early-onset Alzheimer's disease, which is thought to be inherited, and the more common late-onset Alzheimer’s. New findings, however, suggest we should re-think that distinction. While the genetic case for early-onset might seem to be stronger, sporadic (non-familial) cases do occur, and familial cases occur with late-onset.

New DNA sequencing techniques applied to the APP (amyloid precursor protein) gene, and the PSEN1 and PSEN2 (presenilin) genes (the three genes linked to early-onset Alzheimer's) has found that rare variants in these genes are more common in families where four or more members were affected with late-onset Alzheimer’s, compared to normal individuals. Additionally, mutations in the MAPT (microtubule associated protein tau) gene and GRN (progranulin) gene (both linked to frontotemporal dementia) were also found in some Alzheimer's patients, suggesting they had been incorrectly diagnosed as having Alzheimer's disease when they instead had frontotemporal dementia.

Of the 439 patients in which at least four individuals per family had been diagnosed with Alzheimer's disease, rare variants in the 3 Alzheimer's-related genes were found in 60 (13.7%) of them. While not all of these variants are known to be pathogenic, the frequency of mutations in these genes is significantly higher than it is in the general population.

The researchers estimate that about 5% of those with late-onset Alzheimer's disease have changes in these genes. They suggest that, at least in some cases, the same causes may underlie both early- and late-onset disease. The difference being that those that develop it later have more protective factors.

Another gene identified in early-onset Alzheimer's

A study of the genes from 130 families suffering from early-onset Alzheimer's disease has found that 116 had mutations on genes already known to be involved (APP, PSEN1, PSEN2 — see below for some older reports on these genes), while five of the other 14 families all showed mutations on a new gene: SORL1.

I say ‘new gene’ because it hasn’t been implicated in early-onset Alzheimer’s before. However, it has been implicated in the more common late-onset Alzheimer’s, and last year a study reported that the gene was associated with differences in hippocampal volume in young, healthy adults.

The finding, then, provides more support for the idea that some cases of early-onset and late-onset Alzheimer’s have the same causes.

The SORL1 gene codes for a protein involved in the production of the beta-amyloid peptide, and the mutations seen in this study appear to cause an under-expression of SORL1, resulting in an increase in the production of the beta-amyloid peptide. Such mutations were not found in the 1500 ethnicity-matched controls.

 

Older news reports on these other early-onset genes (brought over from the old website):

New genetic cause of Alzheimer's disease

Amyloid protein originates when it is cut by enzymes from a larger precursor protein. In very rare cases, mutations appear in the amyloid precursor protein (APP), causing it to change shape and be cut differently. The amyloid protein that is formed now has different characteristics, causing it to begin to stick together and precipitate as amyloid plaques. A genetic study of Alzheimer's patients younger than 70 has found genetic variations in the promoter that increases the gene expression and thus the formation of the amyloid precursor protein. The higher the expression (up to 150% as in Down syndrome), the younger the patient (starting between 50 and 60 years of age). Thus, the amount of amyloid precursor protein is a genetic risk factor for Alzheimer's disease.

Theuns, J. et al. 2006. Promoter Mutations That Increase Amyloid Precursor-Protein Expression Are Associated with Alzheimer Disease. American Journal of Human Genetics, 78, 936-946.

http://www.eurekalert.org/pub_releases/2006-04/vfii-rda041906.php

Evidence that Alzheimer's protein switches on genes

Amyloid b-protein precursor (APP) is snipped apart by enzymes to produce three protein fragments. Two fragments remain outside the cell and one stays inside. When APP is produced in excessive quantities, one of the cleaved segments that remains outside the cell, called the amyloid b-peptides, clumps together to form amyloid plaques that kill brain cells and may lead to the development of Alzheimer’s disease. New research indicates that the short "tail" segment of APP that is trapped inside the cell might also contribute to Alzheimer’s disease, through a process called transcriptional activation - switching on genes within the cell. Researchers speculate that creation of amyloid plaque is a byproduct of a misregulation in normal APP processing.

[2866] Cao X, Südhof TC. A Transcriptively Active Complex of APP with Fe65 and Histone Acetyltransferase Tip60. Science [Internet]. 2001 ;293(5527):115 - 120. Available from: http://www.sciencemag.org/content/293/5527/115

http://www.eurekalert.org/pub_releases/2001-07/aaft-eta070201.php

Inactivation of Alzheimer's genes in mice causes dementia and brain degeneration

Mutations in two related genes known as presenilins are the major cause of early onset, inherited forms of Alzheimer's disease, but how these mutations cause the disease has not been clear. Since presenilins are involved in the production of amyloid peptides (the major components of amyloid plaques), it was thought that such mutations might cause Alzheimer’s by increasing brain levels of amyloid peptides. Accordingly, much effort has gone into identifying compounds that could block presenilin function. Now, however, genetic engineering in mice has revealed that deletion of these genes causes memory loss and gradual death of nerve cells in the mouse brain, demonstrating that the protein products of these genes are essential for normal learning, memory and nerve cell survival.

Saura, C.A., Choi, S-Y., Beglopoulos, V., Malkani, S., Zhang, D., Shankaranarayana Rao, B.S., Chattarji, S., Kelleher, R.J.III, Kandel, E.R., Duff, K., Kirkwood, A. & Shen, J. 2004. Loss of Presenilin Function Causes Impairments of Memory and Synaptic Plasticity Followed by Age-Dependent Neurodegeneration. Neuron, 42 (1), 23-36.

http://www.eurekalert.org/pub_releases/2004-04/cp-ioa032904.php

Reference: 

[2858] Consortium ENIGM-A (ENIGMA), Cohorts Heart Aging Research Genomic Epidemiology (charge). Common variants at 12q14 and 12q24 are associated with hippocampal volume. Nature Genetics [Internet]. 2012 ;44(5):545 - 551. Available from: http://www.nature.com/ng/journal/v44/n5/full/ng.2237.html

[2909] Taal RH, Pourcain BS, Thiering E, Das S, Mook-Kanamori DO, Warrington NM, Kaakinen M, Kreiner-Møller E, Bradfield JP, Freathy RM, et al. Common variants at 12q15 and 12q24 are associated with infant head circumference. Nature Genetics [Internet]. 2012 ;44(5):532 - 538. Available from: http://www.nature.com/ng/journal/v44/n5/abs/ng.2238.html

[2859] Cohorts Heart Aging Research Genomic Epidemiology (charge), Consortium EGG (EGG). Common variants at 6q22 and 17q21 are associated with intracranial volume. Nature Genetics [Internet]. 2012 ;44(5):539 - 544. Available from: http://www.nature.com/ng/journal/v44/n5/full/ng.2245.html

[2907] Stein JL, Medland SE, Vasquez AA, Hibar DP, Senstad RE, Winkler AM, Toro R, Appel K, Bartecek R, Bergmann Ø, et al. Identification of common variants associated with human hippocampal and intracranial volumes. Nature Genetics [Internet]. 2012 ;44(5):552 - 561. Available from: http://www.nature.com/ng/journal/v44/n5/abs/ng.2250.html

[2925] Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z, Holtzman DM, Betsholtz C, Armulik A, Sallstrom J, et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature [Internet]. 2012 . Available from: http://www.nature.com/nature/journal/vaop/ncurrent/full/nature11087.html?WT.ec_id=NATURE-20120517

Kang, J. H., & Grodstein F. (2012).  Postmenopausal hormone therapy, timing of initiation, APOE and cognitive decline. Neurobiology of Aging. 33(7), 1129 - 1137.

Skoog, I., Olesen P. J., Blennow K., Palmertz B., Johnson S. C., & Bigler E. D. (2012).  Head size may modify the impact of white matter lesions on dementia. Neurobiology of Aging. 33(7), 1186 - 1193.

[2728] Cruchaga C, Chakraverty S, Mayo K, Vallania FLM, Mitra RD, Faber K, Williamson J, Bird T, Diaz-Arrastia R, Foroud TM, et al. Rare Variants in APP, PSEN1 and PSEN2 Increase Risk for AD in Late-Onset Alzheimer's Disease Families. PLoS ONE [Internet]. 2012 ;7(2):e31039 - e31039. Available from: UR - http://dx.doi.org/10.1371/journal.pone.0031039,http://dx.doi.org/10.1371/journal.pone.0031039

Full text available at http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0031039

[2897] Pottier C, Hannequin D, Coutant S, Rovelet-Lecrux A, Wallon D, Rousseau S, Legallic S, Paquet C, Bombois S, Pariente J, et al. High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease. Molecular Psychiatry [Internet]. 2012 . Available from: http://www.nature.com/mp/journal/vaop/ncurrent/full/mp201215a.html

McCarthy, J. J., Saith S., Linnertz C., Burke J. R., Hulette C. M., Welsh-Bohmer K. A., et al. (2012).  The Alzheimer's associated 5′ region of the SORL1 gene cis regulates SORL1 transcripts expression. Neurobiology of Aging. 33(7), 1485.e1-1485.e8 - 1485.e1-1485.e8

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Latest London taxi driver study shows brain changes driven by learning

January, 2012

A comparison of the brains of London taxi drivers before and after their lengthy training shows clearly that the increase in hippocampal gray matter develops with training, but this may come at the expense of other brain functions.

The evidence that adult brains could grow new neurons was a game-changer, and has spawned all manner of products to try and stimulate such neurogenesis, to help fight back against age-related cognitive decline and even dementia. An important study in the evidence for the role of experience and training in growing new neurons was Maguire’s celebrated study of London taxi drivers, back in 2000.

The small study, involving 16 male, right-handed taxi drivers with an average experience of 14.3 years (range 1.5 to 42 years), found that the taxi drivers had significantly more grey matter (neurons) in the posterior hippocampus than matched controls, while the controls showed relatively more grey matter in the anterior hippocampus. Overall, these balanced out, so that the volume of the hippocampus as a whole wasn’t different for the two groups. The volume in the right posterior hippocampus correlated with the amount of experience the driver had (the correlation remained after age was accounted for).

The posterior hippocampus is preferentially involved in spatial navigation. The fact that only the right posterior hippocampus showed an experience-linked increase suggests that the right and left posterior hippocampi are involved in spatial navigation in different ways. The decrease in anterior volume suggests that the need to store increasingly detailed spatial maps brings about a reorganization of the hippocampus.

But (although the experience-related correlation is certainly indicative) it could be that those who manage to become licensed taxi drivers in London are those who have some innate advantage, evidenced in a more developed posterior hippocampus. Only around half of those who go through the strenuous training program succeed in qualifying — London taxi drivers are unique in the world for being required to pass through a lengthy training period and pass stringent exams, demonstrating their knowledge of London’s 25,000 streets and their idiosyncratic layout, plus 20,000 landmarks.

In this new study, Maguire and her colleague made a more direct test of this question. 79 trainee taxi drivers and 31 controls took cognitive tests and had their brains scanned at two time points: at the beginning of training, and 3-4 years later. Of the 79 would-be taxi drivers, only 39 qualified, giving the researchers three groups to compare.

There were no differences in cognitive performance or brain scans between the three groups at time 1 (before training). At time 2 however, when the trainees had either passed the test or failed to acquire the Knowledge, those trainees that qualified had significantly more gray matter in the posterior hippocampus than they had had previously. There was no change in those who failed to qualify or in the controls.

Unsurprisingly, both qualified and non-qualified trainees were significantly better at judging the spatial relations between London landmarks than the control group. However, qualified trainees – but not the trainees who failed to qualify – were worse than the other groups at recalling a complex visual figure after 30 minutes (see here for an example of such a figure). Such a finding replicates previous findings of London taxi drivers. In other words, their improvement in spatial memory as it pertains to London seems to have come at a cost.

Interestingly, there was no detectable difference in the structure of the anterior hippocampus, suggesting that these changes develop later, in response to changes in the posterior hippocampus. However, the poorer performance on the complex figure test may be an early sign of changes in the anterior hippocampus that are not yet measurable in a MRI.

The ‘Knowledge’, as it is known, provides a lovely real-world example of expertise. Unlike most other examples of expertise development (e.g. music, chess), it is largely unaffected by childhood experience (there may be some London taxi drivers who began deliberately working on their knowledge of London streets in childhood, but it is surely not common!); it is developed through a training program over a limited time period common to all participants; and its participants are of average IQ and education (average school-leaving age was around 16.7 years for all groups; average verbal IQ was around or just below 100).

So what underlies this development of the posterior hippocampus? If the qualified and non-qualified trainees were comparable in education and IQ, what determined whether a trainee would ‘build up’ his hippocampus and pass the exams? The obvious answer is hard work / dedication, and this is borne out by the fact that, although the two groups were similar in the length of their training period, those who qualified spent significantly more time training every week (an average of 34.5 hours a week vs 16.7 hours). Those who qualified also attended far more tests (an average of 15.6 vs 2.6).

While neurogenesis is probably involved in this growth within the posterior hippocampus, it is also possible that growth reflects increases in the number of connections, or in the number of glia. Most probably (I think), all are involved.

There are two important points to take away from this study. One is its clear demonstration that training can produce measurable changes in a brain region. The other is the indication that this development may come at the expense of other regions (and functions).

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One cause of damage in older brains, and how exercise can help

September, 2011

Two mice studies indicate that an increase in a protein involved in immune response may be behind the reduced ability of older brains to create new neurons, and that exercise produces a protein that helps protect against damage caused by illness, injury, surgery and pollutants.

In the first mouse study, when young and old mice were conjoined, allowing blood to flow between the two, the young mice showed a decrease in neurogenesis while the old mice showed an increase. When blood plasma was then taken from old mice and injected into young mice, there was a similar decrease in neurogenesis, and impairments in memory and learning.

Analysis of the concentrations of blood proteins in the conjoined animals revealed the chemokine (a type of cytokine) whose level in the blood showed the biggest change — CCL11, or eotaxin. When this was injected into young mice, they indeed showed a decrease in neurogenesis, and this was reversed once an antibody for the chemokine was injected. Blood levels of CCL11 were found to increase with age in both mice and humans.

The chemokine was a surprise, because to date the only known role of CCL11 is that of attracting immune cells involved in allergy and asthma. It is thought that most likely it doesn’t have a direct effect on neurogenesis, but has its effect through, perhaps, triggering immune cells to produce inflammation.

Exercise is known to at least partially reverse loss of neurogenesis. Exercise has also been shown to produce chemicals that prevent inflammation. Following research showing that exercise after brain injury can help the brain repair itself, another mouse study has found that mice who exercised regularly produced interleukin-6 (a cytokine involved in immune response) in the hippocampus. When the mice were then exposed to a chemical that destroys the hippocampus, the interleukin-6 dampened the harmful inflammatory response, and prevented the loss of function that is usually observed.

One of the actions of interleukin-6 that brings about a reduction in inflammation is to inhibit tumor necrosis factor. Interestingly, I previously reported on a finding that inhibiting tumor necrosis factor in mice decreased cognitive decline that often follows surgery.

This suggests not only that exercise helps protect the brain from the damage caused by inflammation, but also that it might help protect against other damage, such as that caused by environmental toxins, injury, or post-surgical cognitive decline. The curry spice cucurmin, and green tea, are also thought to inhibit tumor necrosis factor.

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More ways exercise can help seniors fight memory loss

September, 2011

A recent study finds that cognitive decline is greater in older adults who have a high salt intake —but only if they’re not physically active. Another finds that older rats who exercise are protected from memory loss caused by bacterial infection.

A three-year study following 1,262 healthy older Canadians (aged 67-84) has found that, among those who exercised little, those who had high-salt diets showed significantly greater cognitive decline. On the bright side, sedentary older adults who had low-salt consumption did not show cognitive decline over the three years. And those who had higher levels of physical activity did not show any association between salt and cognition.

Low sodium intake is associated with reduced blood pressure and risk of heart disease, adding even more weight to the mantra: what’s good for the heart is good for the brain.

The analysis controlled for age, sex, education, waist circumference, diabetes, and dietary intakes. Salt intake was based on a food frequency questionnaire. Low sodium intake was defined as not exceeding 2,263 mg/day; mid sodium intake 3,090 mg/day; and high sodium intake 3,091 and greater mg/day. A third of the participants fell into each group. Physical activity was also measured by a self-reported questionnaire (Physical Activity Scale for the Elderly). Cognitive function was measured by the Modified MMSE.

And adding to the evidence that exercise is good for you (not that we really need any more!), a rat study has found that aging rats that ran just over half a kilometer each week were protected against long-term memory loss that can happen suddenly following bacterial infection.

Previous research found that older rats experienced memory loss following E. coli infection, but young adult rats did not. In the older animals, microglia (the brain’s immune cells) were more sensitive to infection, releasing greater quantities of inflammatory molecules called cytokines in the hippocampus. This exaggerated response brought about impairments in synaptic plasticity (the neural changes that underlie learning) and reductions in BDNF.

In this study, the rats were given unlimited access to running wheels. Although the old rats only ran an average of 0.43 miles per week (50 times less distance than the young rats), they performed better on a memory test than rats who only had access to a locked exercise wheel. Moreover, the runners performed as well on the memory test as rats that were not exposed to E. coli.

The researchers are now planning to examine the role that stress hormones may play in sensitizing microglia, and whether physical exercise slows these hormones in older rats.

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Why our brains produce fewer new neurons in old age

August, 2011

New research explains why fewer new brain cells are created in the hippocampus as we get older.

It wasn’t so long ago we believed that only young brains could make neurons, that once a brain was fully matured all it could do was increase its connections. Then we found out adult brains could make new neurons too (but only in a couple of regions, albeit critical ones). Now we know that neurogenesis in the hippocampus is vital for some operations, and that the production of new neurons declines with age (leading to the idea that the reduction in neurogenesis may be one reason for age-related cognitive decline).

What we didn’t know is why this happens. A new study, using mice genetically engineered so that different classes of brain cells light up in different colors, has now revealed the life cycle of stem cells in the brain.

Adult stem cells differentiate into progenitor cells that ultimately give rise to mature neurons. It had been thought that the stem cell population remained stable, but that these stem cells gradually lose their ability to produce neurons. However, the mouse study reveals that during the mouse's life span, the number of brain stem cells decreased 100-fold. Although the rate of this decrease actually slows with age, and the output per cell (the number of progenitor cells each stem cell produces) increases, nevertheless the pool of stem cells is dramatically reduced over time.

The reason this happens (and why it wasn’t what we expected) is explained in a computational model developed from the data. It seems that stem cells in the brain differ from other stem cells. Adult stem cells in the brain wait patiently for a long time until they are activated. They then undergo a series of rapid divisions that give rise to progeny that differentiate into neurons, before ‘retiring’ to become astrocytes. What this means is that, unlike blood or gut stem cells (that renew themselves many times), brain stem cells are only used once.

This raises a somewhat worrying question: if we encourage neurogenesis (e.g. by exercise or drugs), are we simply using up stem cells prematurely? The researchers suggest the answer depends on how the neurogenesis has been induced. Parkinson's disease and traumatic brain injury, for example, activate stem cells directly, and so may reduce the stem cell population. However, interventions such as exercise stimulate the progenitor cells, not the stem cells themselves.

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Air pollution impacts cognitive performance

July, 2011

A study of Michigan public schools, and a mouse study, add to growing evidence that high levels of air pollution negatively affect learning and memory.

Following several recent studies pointing to the negative effect of air pollution on children’s cognitive performance (see this April 2010 news report and this May 2011 report), a study of public schools in Michigan has found that 62.5% of the 3660 schools in the state are located in areas with high levels of industrial pollution, and those in areas with the highest industrial air pollution levels had the lowest attendance rates and the highest proportions of students who failed to meet state educational testing standards in English and math. Attendance rates are a potential indicator of health levels.

Minority students were especially hit by this — 81.5% of African American and 62.1% of Hispanic students attend schools in the top 10% of the most polluted areas, compared to 44.4% of white students.

Almost all (95%) of the industrial air pollution around schools comes from 12 chemicals (diisocyanates, manganese, sulfuric acid, nickel, chlorine, chromium, trimethylbenzene, hydrochloric acid, molybdenum trioxide, lead, cobalt and glycol ethers) that are all implicated in negative health effects, including increased risk of respiratory, cardiovascular, developmental and neurological disorders, as well as cancer.

There are potentially two issues here: the first is that air pollution causes health issues which lower school attendance and thus impacts academic performance; the other is that the pollution also directly effects the brain, thus affecting cognitive performance.

A new mouse study looking at the effects of air pollution on learning and memory has now found that male mice exposed to polluted air for six hours a day, five days a week for 10 months (nearly half their lifespan), performed significantly more poorly on learning and memory tasks than those male mice living in filtered air. They also showed more signs of anxiety- and depressive-like behaviors.

These changes in behavior and cognition were linked to clear differences in the hippocampus — those exposed to polluted air had fewer dendritic spines in parts of the hippocampus (CA1 and CA3 regions), shorter dendrites and overall reduced cell complexity. Previous mouse research has also found that such pollution causes widespread inflammation in the body, and can be linked to high blood pressure, diabetes and obesity. In the present study, the same low-grade inflammation was found in the hippocampus. The hippocampus is particularly sensitive to damage caused by inflammation.

The level of pollution the mice were exposed to was equivalent to what people may be exposed to in some polluted urban areas.

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