brain atrophy

Diabetes duration and severity associated with brain atrophy

A study involving 614 patients with type 2 diabetes (mean age 62) has found that longer duration of diabetes was associated with more brain volume loss, particularly in the gray matter. Roughly, for every 10 years of diabetes, the brain was similar to that of a non-diabetic person who was two years older.

However, the study did not confirm any association of diabetes characteristics with small vessel ischemic disease.

http://www.eurekalert.org/pub_releases/2014-04/rson-dda042214.php

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Cognitive decline in old age related to poorer sleep

February, 2013
  • A new study confirms the role slow-wave sleep plays in consolidating memories, and reveals that one reason for older adults’ memory problems may be the quality of their sleep.

Recent research has suggested that sleep problems might be a risk factor in developing Alzheimer’s, and in mild cognitive impairment. A new study adds to this gathering evidence by connecting reduced slow-wave sleep in older adults to brain atrophy and poorer learning.

The study involved 18 healthy young adults (mostly in their 20s) and 15 healthy older adults (mostly in their 70s). Participants learned 120 word- nonsense word pairs and were tested for recognition before going to bed. Their brain activity was recorded while they slept. Brain activity was also measured in the morning, when they were tested again on the word pairs.

As has been found previously, older adults showed markedly less slow-wave activity (both over the whole brain and specifically in the prefrontal cortex) than the younger adults. Again, as in previous studies, the biggest difference between young and older adults in terms of gray matter volume was found in the medial prefrontal cortex (mPFC). Moreover, significant differences were also found in the insula and posterior cingulate cortex. These regions, like the mPFC, have also been associated with the generation of slow waves.

When mPFC volume was taken into account, age no longer significantly predicted the extent of the decline in slow-wave activity — in other words, the decline in slow-wave activity appears to be due to the brain atrophy in the medial prefrontal cortex. Atrophy in other regions of the brain (precuneus, hippocampus, temporal lobe) was not associated with the decline in slow-wave activity when age was considered.

Older adults did significantly worse on the delayed recognition test than young adults. Performance on the immediate test did not predict performance on the delayed test. Moreover, the highest performers on the immediate test among the older adults performed at the same level as the lowest young adult performers — nevertheless, these older adults did worse the following day.

Slow-wave activity during sleep was significantly associated with performance on the next day’s test. Moreover, when slow-wave activity was taken into account, neither age nor mPFC atrophy significantly predicted test performance.

In other words, age relates to shrinkage of the prefrontal cortex, this shrinkage relates to a decline in slow-wave activity during sleep, and this decline in slow-wave sleep relates to poorer cognitive performance.

The findings confirm the importance of slow-wave brainwaves for memory consolidation.

All of this suggests that poorer sleep quality contributes significantly to age-related cognitive decline, and that efforts should be made to improve quality of sleep rather than just assuming lighter, more disturbed sleep is ‘natural’ in old age!

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Exercise may be best way to protect against brain shrinkage

November, 2012
  • A large study of older adults shows that physical exercise is associated with less brain atrophy and fewer white matter lesions. A small study shows that frail seniors benefit equally from exercise.

A study using data from the Lothian Birth Cohort (people born in Scotland in 1936) has analyzed brain scans of 638 participants when they were 73 years old. Comparing this data with participants’ earlier reports of their exercise and leisure activities at age 70, it was found that those who reported higher levels of regular physical activity showed significantly less brain atrophy than those who did minimal exercise. Participation in social and mentally stimulating activities, on the other hand, wasn’t associated with differences in brain atrophy.

Regular physical exercise was also associated with fewer white matter lesions. While leisure activity was also associated with healthier white matter, this was not significant after factors such as age, social class, and health status were taken into account.

Unfortunately, this study is reported in a journal to which I don’t have access. I would love to have more details about the leisure activities data and the brain scans. However, although the failure to find a positive effect of stimulating activities is disappointing, it’s worth noting another recent study, that produced two relevant findings. First, men with high levels of cognitive activity showed a significant reduction in white matter lesions, while women did not. Women with high levels of cognitive activity, on the other hand, showed less overall brain atrophy — but men did not.

Secondly, both genders showed less atrophy in a particular region of the prefrontal cortex, but there was no effect on the hippocampus — the natural place to look for effects (and the region where physical exercise is known to have positive effects).

In other words, the positive effects of cognitive activity on the brain might be quite different from the positive effects of physical exercise.

The findings do, of course, add to the now-compelling evidence for the benefits of regular physical activity in fighting cognitive decline.

It’s good news, then, that a small study has found that even frail seniors can derive significant benefits from exercise.

The study involved 83 older adults (61-89), some of whom were considered frail. Forty-three took part in group exercises (3 times a week for 12 weeks), while 40 were wait-listed controls. Participants were assessed for physical capacity, quality of life and cognitive health a week before the program began, and at the end.

Those who took part in the exercise program significantly improved their physical capacity, cognitive performance, and quality of life. These benefits were equivalent among frail and non-frail participants.

Frailty is associated with a higher risk of falls, hospitalizations, cognitive decline and psychological distress, and, of course, increases with age. In the U.S, it’s estimated that 7% of seniors aged 65 to 74, 18% of those aged 75 to 84, and 37% of seniors over the age of 85 are frail.

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Alzheimer’s biomarkers present decades before symptoms

July, 2012
  • People with a strong genetic risk of early-onset Alzheimer’s have revealed a progression of brain changes that begin 25 years before symptoms are evident.

A study involving those with a strong genetic risk of developing Alzheimer’s has found that the first signs of the disease can be detected 25 years before symptoms are evident. Whether this is also true of those who develop the disease without having such a strong genetic predisposition is not yet known.

The study involved 128 individuals with a 50% chance of inheriting one of three mutations that are certain to cause Alzheimer’s, often at an unusually young age. On the basis of participants’ parents’ medical history, an estimate of age of onset was calculated.

The first observable brain marker was a drop in cerebrospinal fluid levels of amyloid-beta proteins, and this could be detected 25 years before the anticipated age of onset. Amyloid plaques in the precuneus became visible on brain scans 15-20 years before memory problems become apparent; elevated cerebrospinal fluid levels of the tau protein 10-15 years, and brain atrophy in the hippocampus 15 years. Ten years before symptoms, the precuneus showed reduced use of glucose, and slight impairments in episodic memory (as measured in the delayed-recall part of the Wechsler’s Logical Memory subtest) were detectable. Global cognitive impairment (measured by the MMSE and the Clinical Dementia Rating scale) was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset.

Family members without the risky genes showed none of these changes.

The risky genes are PSEN1 (present in 70 participants), PSEN2 (11), and APP (7) — note that together these account for 30-50% of early-onset familial Alzheimer’s, although only 0.5% of Alzheimer’s in general. The ‘Alzheimer’s gene’ APOe4 (which is a risk factor for sporadic, not familial, Alzheimer’s), was no more likely to be present in these carriers (25%) than noncarriers (22%), and there were no gender differences. The average parental age of symptom onset was 46 (note that this pushes back the first biomarker to 21! Can we speculate a connection to noncarriers having significantly more education than carriers — 15 years vs 13.9?).

The results paint a clear picture of how Alzheimer’s progresses, at least in this particular pathway. First come increases in the amyloid-beta protein, followed by amyloid pathology, tau pathology, brain atrophy, and decreased glucose metabolism. Following this biological cascade, cognitive impairment ensues.

The degree to which these findings apply to the far more common sporadic Alzheimer’s is not known, but evidence from other research is consistent with this progression.

It must be noted, however, that the findings are based on cross-sectional data — that is, pieced together from individuals at different ages and stages. A longitudinal study is needed to confirm.

The findings do suggest the importance of targeting the first step in the cascade — the over-production of amyloid-beta — at a very early stage.

Researchers encourage people with a family history of multiple generations of Alzheimer’s diagnosed before age 55 to register at http://www.DIANXR.org/, if they would like to be considered for inclusion in any research.

Reference: 

[2997] Bateman, R. J., Xiong C., Benzinger T. L. S., Fagan A. M., Goate A., Fox N. C., et al.
(2012).  Clinical and Biomarker Changes in Dominantly Inherited Alzheimer's Disease.
New England Journal of Medicine. 120723122607004 - 120723122607004.

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Effect of blood pressure on the aging brain depends on genetics

July, 2012
  • For those with the Alzheimer’s gene, higher blood pressure, even though within the normal range, is linked to greater brain shrinkage and reduced cognitive ability.

I’ve reported before on the evidence suggesting that carriers of the ‘Alzheimer’s gene’, APOE4, tend to have smaller brain volumes and perform worse on cognitive tests, despite being cognitively ‘normal’. However, the research hasn’t been consistent, and now a new study suggests the reason.

The e4 variant of the apolipoprotein (APOE) gene not only increases the risk of dementia, but also of cardiovascular disease. These effects are not unrelated. Apoliproprotein is involved in the transportation of cholesterol. In older adults, it has been shown that other vascular risk factors (such as elevated cholesterol, hypertension or diabetes) worsen the cognitive effects of having this gene variant.

This new study extends the finding, by looking at 72 healthy adults from a wide age range (19-77).

Participants were tested on various cognitive abilities known to be sensitive to aging and the effects of the e4 allele. Those abilities include speed of information processing, working memory and episodic memory. Blood pressure, brain scans, and of course genetic tests, were also performed.

There are a number of interesting findings:

  • The relationship between age and hippocampal volume was stronger for those carrying the e4 allele (shrinkage of this brain region occurs with age, and is significantly greater in those with MCI or dementia).
  • Higher systolic blood pressure was significantly associated with greater atrophy (i.e., smaller volumes), slower processing speed, and reduced working memory capacity — but only for those with the e4 variant.
  • Among those with the better and more common e3 variant, working memory was associated with lateral prefrontal cortex volume and with processing speed. Greater age was associated with higher systolic blood pressure, smaller volumes of the prefrontal cortex and prefrontal white matter, and slower processing. However, blood pressure was not itself associated with either brain atrophy or slower cognition.
  • For those with the Alzheimer’s variant (e4), older adults with higher blood pressure had smaller volumes of prefrontal white matter, and this in turn was associated with slower speed, which in turn linked to reduced working memory.

In other words, for those with the Alzheimer’s gene, age differences in working memory (which underpin so much of age-related cognitive impairment) were produced by higher blood pressure, reduced prefrontal white matter, and slower processing. For those without the gene, age differences in working memory were produced by reduced prefrontal cortex and prefrontal white matter.

Most importantly, these increases in blood pressure that we are talking about are well within the normal range (although at the higher end).

The researchers make an interesting point: that these findings are in line with “growing evidence that ‘normal’ should be viewed in the context of individual’s genetic predisposition”.

What it comes down to is this: those with the Alzheimer’s gene variant (and no doubt other genetic variants) have a greater vulnerability to some of the risk factors that commonly increase as we age. Those with a family history of dementia or serious cognitive impairment should therefore pay particular attention to controlling vascular risk factors, such as hypertension and diabetes.

This doesn’t mean that those without such a family history can safely ignore such conditions! When they get to the point of being clinically diagnosed as problems, then they are assuredly problems for your brain regardless of your genetics. What this study tells us is that these vascular issues appear to be problematic for Alzheimer’s gene carriers before they get to that point of clinical diagnosis.

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Eye health related to brain health in older adults

June, 2012
  • A large, long-running study has found cognitive decline and brain lesions are linked to mild retinal damage in older women.

Damage to the retina (retinopathy) doesn’t produce noticeable symptoms in the early stages, but a new study indicates it may be a symptom of more widespread damage. In the ten-year study, involving 511 older women (average age 69), 7.6% (39) were found to have retinopathy. These women tended to have lower cognitive performance, and brain scans revealed that they had more areas of small vascular damage within the brain — 47% more overall, and 68% more in the parietal lobe specifically. They also had more white matter damage. They did not have any more brain atrophy.

These correlations remained after high blood pressure and diabetes (the two major risk factors for retinopathy) were taken into account. It’s estimated that 40-45% of those with diabetes have retinopathy.

Those with retinopathy performed similarly to those without on a visual acuity test. However, testing for retinopathy is a simple test that should routinely be carried out by an optometrist in older adults, or those with diabetes or hypertension.

The findings suggest that eye screening could identify developing vascular damage in the brain, enabling lifestyle or drug interventions to begin earlier, when they could do most good. The findings also add to the reasons why you shouldn’t ignore pre-hypertensive and pre-diabetic conditions.

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How cognitive reserve helps protect seniors from cognitive decline

May, 2012
  • Greater cognitive activity doesn’t appear to prevent Alzheimer’s brain damage, but is associated with more neurons in the prefrontal lobe, as well as other gender-specific benefits.

Data from the very large and long-running Cognitive Function and Ageing Study, a U.K. study involving 13,004 older adults (65+), from which 329 brains are now available for analysis, has found that cognitive lifestyle score (CLS) had no effect on Alzheimer’s pathology. Characteristics typical of Alzheimer’s, such as plaques, neurofibrillary tangles, and hippocampal atrophy, were similar in all CLS groups.

However, while cognitive lifestyle may have no effect on the development of Alzheimer's pathology, that is not to say it has no effect on the brain. In men, an active cognitive lifestyle was associated with less microvascular disease. In particular, the high CLS group showed an 80% relative reduction in deep white matter lesions. These associations remained after taking into account cardiovascular risk factors and APOE status.

This association was not found in women. However, women in the high CLS group tended to have greater brain weight.

In both genders, high CLS was associated with greater neuronal density and cortical thickness in Brodmann area 9 in the prefrontal lobe (but not, interestingly, in the hippocampus).

Cognitive lifestyle score is produced from years of education, occupational complexity coded according to social class and socioeconomic grouping, and social engagement based on frequency of contact with relatives, neighbors, and social events.

The findings provide more support for the ‘cognitive reserve’ theory, and shed some light on the mechanism, which appears to be rather different than we imagined. It may be that the changes in the prefrontal lobe (that we expected to see in the hippocampus) are a sign that greater cognitive activity helps you develop compensatory networks, rather than building up established ones. This would be consistent with research suggesting that older adults who maintain their cognitive fitness do so by developing new strategies that involve different regions, compensating for failing regions.

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Being active reduces Alzheimer's risk

May, 2012
  • A large study provides evidence that higher levels of everyday activity help prevent Alzheimer’s, although more intense activity is even better.

A four-year study involving 716 elderly (average age 82) has revealed that those who were most physically active were significantly less likely to develop Alzheimer’s than those least active. The study is unique in that, in addition to self-reports of physical and social activity, activity was objectively measured (for up to 10 days) through a device worn on the wrist. This device (an actigraph) enabled everyday activity, such as cooking, washing the dishes, playing cards and even moving a wheelchair with a person's arms, to be included in the analysis.

Cognitive performance was assessed annually. Over the study period, 71 participants (10%) developed Alzheimer’s.

The study found that those in the bottom 10% of daily physical activity were more than twice as likely (2.3 times) to develop Alzheimer's disease as those in the top 10%. Those in the bottom 10% of intensity of physical activity were almost three times (2.8 times) as likely to develop Alzheimer's disease as people in the top 10%.

Moreover, the level of activity was associated with the rate of cognitive decline.

The association remained after motor function, depression, chronic health conditions, and APOE gene status were taken into account.

The findings should encourage anyone who feels that physical exercise is beyond them to nevertheless engage in milder forms of daily activity.

 

Addendum:

Another recent study, involving 331 cognitively healthy elderly, has also found that higher levels of physical activity were associated with better cognitive performance (specifically, a shorter time to complete the Trail-making test, and higher levels of verbal fluency) and less brain atrophy. Activity levels were based on the number of self-reported light and hard activities for at least 30 minutes per week. Participants were assessed in terms of MMSE score, verbal fluency, and visuospatial ability.

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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 T. C.
(2001).  A Transcriptively Active Complex of APP with Fe65 and Histone Acetyltransferase Tip60.
Science. 293(5527), 115 - 120.

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, E N I G M-A(ENIGMA)., & Cohorts Heart Aging Research Genomic Epidemiology(charge)
(2012).  Common variants at 12q14 and 12q24 are associated with hippocampal volume.
Nature Genetics. 44(5), 545 - 551.

[2909] Taal, R. H., Pourcain B S., Thiering E., Das S., Mook-Kanamori D. O., Warrington N. M., et al.
(2012).  Common variants at 12q15 and 12q24 are associated with infant head circumference.
Nature Genetics. 44(5), 532 - 538.

[2859] Cohorts Heart Aging Research Genomic Epidemiology,(charge), & Consortium E G G(EGG).
(2012).  Common variants at 6q22 and 17q21 are associated with intracranial volume.
Nature Genetics. 44(5), 539 - 544.

[2907] Stein, J. L., Medland S. E., Vasquez A A., Hibar D. P., Senstad R. E., Winkler A. M., et al.
(2012).  Identification of common variants associated with human hippocampal and intracranial volumes.
Nature Genetics. 44(5), 552 - 561.

[2925] Bell, R. D., Winkler E. A., Singh I., Sagare A. P., Deane R., Wu Z., et al.
(2012).  Apolipoprotein E controls cerebrovascular integrity via cyclophilin A.
Nature.

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 F. L. M., Mitra R. D., Faber K., et al.
(2012).  Rare Variants in APP, PSEN1 and PSEN2 Increase Risk for AD in Late-Onset Alzheimer's Disease Families.
PLoS ONE. 7(2), e31039 - e31039.

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., et al.
(2012).  High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease.
Molecular Psychiatry.

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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Low levels of omega-3 fatty acids linked to brain aging

April, 2012
  • A large study has found that older adults with low levels of omega-3 fatty acids had greater brain atrophy and more white matter damage.

A study involving 1,575 older adults (aged 58-76) has found that those with DHA levels in the bottom 25% had smaller brain volume (equivalent to about 2 years of aging) and greater amounts of white matter lesions. Those with levels of all omega-3 fatty acids in the bottom quarter also scored lower on tests of visual memory, executive function, and abstract thinking.

The finding adds to the evidence that higher levels of omega-3 fatty acids reduce dementia risk.

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