Alzheimer's & other dementias
Here’s a different aspect to cognitive reserve. I have earlier reported on the first tranche of results from this study. Now new results, involving 246 older adults from the Rush Memory and Aging Project, have confirmed earlier findings that having a greater purpose in life may help protect against the brain damage wrought by Alzheimer’s disease.
Participants received an annual clinical evaluation for up to 10 years, which included detailed cognitive testing and neurological exams. They were also interviewed about their purpose in life, that is, the degree to which they derived meaning from life's experiences and were focused and intentional. After death (average age 88), their brains were examined for Alzheimer’s pathology.
Cognitive function, unsurprisingly, declined progressively with increased Alzheimer’s pathology (such as amyloid plaque and tau tangles). But ‘purpose in life’ modified this association, with higher levels of purposiveness reducing the effect of pathology on cognition. The effect was strongest for those with the greatest damage (especially tangles).
The analysis took into account depression, APOE gene status, and other relevant medical factors.
 Boyle, P. A., Buchman A. S., Wilson R. S., Yu L., Schneider J. A., & Bennett D. A.
(2012). Effect of Purpose in Life on the Relation Between Alzheimer Disease Pathologic Changes on Cognitive Function in Advanced Age.
Archives of General Psychiatry. 69(5), 499 - 504.
A small study supports the view that excess activity in the hippocampus seen in aMCI is not compensatory but a sign of dysfunction, and shows that an epileptic drug reduces activity and improves memory.
Interpreting brain activity is a very tricky business. Even the most basic difference can be interpreted in two ways — i.e., what does it mean if a region is more active in one group of people compared to another? A new study not only indicates a new therapeutic approach to amnestic mild cognitive impairment, but also demonstrates the folly of assuming that greater activity is good.
Higher activity in the dentate gyrus/CA3 region of the hippocampus is often seen in disorders associated with an increased Alzheimer's risk, such as aMCI. It’s been thought, reasonably enough, that this might reflect compensatory activity, as the brain recruits extra resources in the face of memory loss. But rodent studies have suggested an alternative interpretation: that the increased activity might itself be part of the problem.
Following on from animal studies, this new study has investigated the effects of a drug that reduces hippocampal hyperactivity. The drug, levetiracetam, is used to treat epilepsy. The 17 patients with aMCI (average age 73) were given a placebo in the first two-week treatment phase and a low dose of the epilepsy drug during the second treatment phase, while 17 controls (average age 69) were given a placebo in both treatment phases. The treatments were separated by four weeks, and brain scans were given at the end of each phase. Participants carried out a cognitive task designed to assess memory errors attributable to a dysfunction in the dentate gyrus/CA3 region (note that these neighboring areas are not clearly demarcated from each other, and so are best analyzed as one).
As predicted, those with aMCI showed greater activity in this region, and treatment with the drug significantly reduced that activity. The drug treatment also significantly improved their performance on the three-choice recognition task, with a significant decrease in memory errors. It did not have a significant effect on general cognition or memory (as measured by delayed recall on the Verbal Paired Associates subtest of the Wechsler Memory Scale, the Benton Visual Retention Test, and the Buschke Selective Reminding Test).
These findings make it clear that the excess activity in the hippocampus is not compensatory, and also point to the therapeutic value of targeting this hyperactivity for those with aMCI. It also raises the possibility that other conditions might benefit from this approach. For example, those who carry the Alzheimer’s gene, APOE4, also show increased hippocampal activity.
 Bakker, A., Krauss G. L., Albert M. S., Speck C. L., Jones L. R., Stark C. E., et al.
(2012). Reduction of Hippocampal Hyperactivity Improves Cognition in Amnestic Mild Cognitive Impairment.
Neuron. 74(3), 467 - 474.
A round-up of genetic news.
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.
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 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).
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.
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):
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.
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.
 Cao, X., & Südhof T. C.
(2001). A Transcriptively Active Complex of APP with Fe65 and Histone Acetyltransferase Tip60.
Science. 293(5527), 115 - 120.
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.
 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.
 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.
 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.
 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.
 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.
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.
 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
 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.
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
Why ‘Alzheimer’s gene’ increases Alzheimer’s risk: http://www.futurity.org/health-medicine/alzheimers-gene-opens-floodgate-in-brain/
More genes involved in Alzheimer’s: Full text available at http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0015918
Same genes linked to early- and late-onset Alzheimer's: http://www.eurekalert.org/pub_releases/2012-02/wuso-sgl020112.php
Another gene identified in early-onset Alzheimer's: http://www.eurekalert.org/pub_releases/2012-04/ind-ang040412.php
A review supports cognitive stimulation therapy for those with mild to moderate dementia.
A review of 15 randomized controlled trials in which people with mild to moderate dementia were offered mental stimulation has concluded that such stimulation does indeed help slow down cognitive decline.
In total, 718 people with mild to moderate dementia, of whom 407 received cognitive stimulation, were included in the meta-analysis. The studies included in the review were identified from a search of the Cochrane Dementia and Cognitive Improvement Group Specialized Register, and included all randomized controlled trials of cognitive stimulation for dementia which incorporated a measure of cognitive change.
Participants were generally treated in small groups and activities ranged from discussions and word games to music and baking. Treatment was compared to those seen without treatment, with "standard treatments" (such as medicine, day care or visits from community mental health workers), or with alternative activities such as watching TV and physical therapy.
There was a “clear, consistent benefit” on cognitive function for those receiving cognitive stimulation, and these benefits were still seen one to three months after the treatment. Benefits were also seen for social interaction, communication and quality of life and well-being.
While no evidence was found for improvements in the mood of participants, or their ability to care for themselves or function independently, or in problem behaviors, this is not to say that lengthier or more frequent interventions might not be beneficial in these areas (that’s purely my own suggestion).
In one study, family members were trained to deliver cognitive stimulation on a one-to-one basis, and the reviewers suggested that this was an approach deserving of further attention.
The reviewers did note that the quality of the studies was variable, with small sample sizes. It should also be noted that this review builds on an earlier review, involving a subset of these studies, in which the opposite conclusion was drawn — that is, at that time, there was insufficient evidence that such interventions helped people with dementia. There is no doubt that larger and lengthier trials are needed, but these new results are very promising.
 Woods, B., Aguirre E., Spector A. E., Orrell M., Woods B., Aguirre E., et al.
(Submitted). Cognitive stimulation to improve cognitive functioning in people with dementia.
The Cochrane Library.
More evidence comes for a link between lower physical fitness and increased risk of dementia in a large study that extends earlier findings to middle-aged and younger-old.
Following on from research showing an association between lower walking speed and increased risk of dementia, and weaker hand grip strength and increased dementia risk, a large study has explored whether this association extends to middle-aged and younger-old adults.
Part of the long-running Framingham study, the study involved 2,410 men and women with an average age of 62, who underwent brain scans and tests for walking speed, hand grip strength and cognitive function. During the follow-up period of up to 11 years, 34 people (1.4%) developed dementia (28 Alzheimer’s) and 79 people (3.3%) had a stroke.
Those who had a slower walking speed at the start of the study were one-and-a-half times more likely to develop dementia compared to people with faster walking speed, while stronger hand grip strength was associated with a 42% lower risk of stroke or transient ischemic attack in people over age 65.
Slower walking speed and weaker hand grip strength were also associated with lower brain volume and poorer cognitive performance. Specifically, those with slower walking speed scored significantly worse on tests of visual reproduction, paired associate learning, executive function, visual organization, and language (Boston Naming test). Higher hand grip strength was associated with higher scores on tests of visual reproduction, executive function, visual organization, language and abstraction (similarities test).
While the nature of the association is not yet understood, the findings do seem to support the benefits of physical fitness. At the least, these physical attributes can serve as pointers to the need for more investigation of an older person’s brain health. But they might also serve as a warning to improve physical fitness.
Camargo, E.C., Beiser, A., Tan, Z.S., Au, R., DeCarli, C., Pikula, A., Kelly-Hayes, M., Kase, C., Wolf, P. & Seshadri, S. 2012. Walking Speed, Handgrip Strength and Risk of Dementia and Stroke: The Framingham Offspring Study. To be presented April 25 at the American Academy of Neurology's 64th Annual Meeting in New Orleans.
A pilot study suggests that wearing a nicotine patch may help improve memory loss in older adults with mild cognitive impairment.
The study involved 74 non-smokers with amnestic MCI (average age 76), of whom half were given a nicotine patch of 15 mg a day for six months and half received a placebo. Cognitive tests were given at the start of the study and again after three and six months.
After 6 months of treatment, the nicotine-treated group showed significant improvement in attention, memory, speed of processing and consistency of processing. For example, the nicotine-treated group regained 46% of normal performance for age on long-term memory, whereas the placebo group worsened by 26%.
Nicotine is an interesting drug, in that, while predominantly harmful, it can have positive effects if the dose is just right, and if the person’s cognitive state is at a particular level (slipping below their normal state, but not too far below). Too much nicotine will make things worse, so it’s important not to self-medicate.
Nicotine has been shown to improve cognitive performance in smokers who have stopped smoking and previous short-term studies with nicotine have shown attention and memory improvement in people with Alzheimer's disease. Nicotine receptors in the brain are reduced in Alzheimer’s brains.
Because the dose is so crucial, and the effects so dependent on brain state (including, one assumes, whether the person has been a smoker or not), more research is needed before this can be used as a treatment.
 Newhouse, P., Kellar K., Aisen P., White H., Wesnes K., Coderre E., et al.
(2012). Nicotine treatment of mild cognitive impairment.
Neurology. 78(2), 91 - 101.
Significant differences in the risk of mild cognitive impairment for men and women, and in the risk of developing the two sub-types, suggests that risk factors should be considered separately for genders and sub-type.
More data from the long-running Mayo Clinic Study of Aging has revealed that, in this one part of the U.S. at least, MCI develops at an overall rate of 6.4% a year among older adults (70+), with a higher rate for men and the less-educated.
The study involved 1,450 older adults (aged 70-89), who underwent memory testing every 15 months for an average of three years. By the end of the study period, 296 people had developed MCI, a rate of 6.4% per year. For men, the rate was 7.2% compared to 5.7% for women.
It should be noted that these rates apply to a relatively homogeneous group of people. Participants come from one county in Minnesota, an overwhelmingly white part of the U.S.
MCI comes in two types: amnestic (involving memory loss) and non-amnestic. Amnestic MCI was more than twice as common as non-amnestic MCI. The incidence rate of aMCI was also higher for men (4.4%) than women (3.3%), as was the risk of naMCI (2% vs 1.1%).
Those who had less education also had higher rates of MCI. For aMCI, the rate for those with 12 years or less of education was 4.3%, compared to 3.25% for those with more education. Similarly, for naMCI, the rates were 2% and 1%, respectively.
While the great majority of people diagnosed with MCI continued to have the disorder or progressed to dementia, some 12% were later re-diagnosed as not having it. This, I would presume, probably reflects temporary ‘dips’ in cognitive performance as a consequence of physical or emotional problems.
The differences between aMCI and naMCI, and between genders, suggest that risk factors for these should be considered separately.
 Roberts, R. O., Geda Y. E., Knopman D. S., Cha R. H., Pankratz V. S., Boeve B. F., et al.
(2012). The incidence of MCI differs by subtype and is higher in men.
Neurology. 78(5), 342 - 351.
Growing evidence points to greater education and mentally stimulating occupations and activities providing a cognitive reserve that enables people with developing Alzheimer's to function normally for longer. Cognitive reserve means that your brain can take more damage before it has noticeable effects. A 2006 review found that some 30% of older adults found to have Alzheimer’s when autopsied had shown no signs of it when alive.
There are two relevant concepts behind the protection some brains have: cognitive reserve (which I have mentioned on a number of occasions), and brain reserve, which is more structural. ‘Brain reserve’ encapsulates the idea that certain characteristics, such as a greater brain size, help protect the brain from damage. Longitudinal studies have provided evidence, for example, that a larger head size in childhood helps reduce the risk of developing Alzheimer’s.
While cognitive reserve has been most often associated with education, it has also been associated with occupation, bilingualism, and music. A new study provides physical evidence for how effective bilingualism is.
The Toronto study involved 40 patients with a diagnosis of probable Alzheimer’s, of whom half were bilingual (fluent in a second language, and consistent users of both languages throughout their lives). Bilingual and monolingual patients were matched on a test of cognitive function (the Behavioral Neurology Assessment). The two groups were similar in education levels, gender, and performance on the MMSE and the clock drawing test. The groups did differ significantly in occupational status, with the monolinguals having higher job status than the bilinguals.
Notwithstanding this similarity in cognitive performance, brain scans revealed that the bilingual group had substantially greater atrophy in the medial temporal lobe and the temporal lobe. The two groups did not differ in measures of central and frontal atrophy, however — these regions are not associated with Alzheimer’s.
In other words, bilingualism seems to specifically help protect those areas implicated in Alzheimers, and the bilinguals could take much greater damage to the brain before it impacted their cognitive performance. It is suggested that the act of constantly switching between languages, or suppressing one language in favor of other, may help train the brain to be more flexible when the need comes to compensate for damaged areas.
The findings are consistent with previous observational studies suggesting that bilingualism delays the onset of Alzheimer's symptoms by up to five years.
 Schweizer, T. A., Ware J., Fischer C. E., Craik F. I. M., & Bialystok E.
(2011). Bilingualism as a contributor to cognitive reserve: Evidence from brain atrophy in Alzheimer’s disease.
Valenzuela MJ and Sachdev P. 2006. Brain reserve and dementia: A systematic review. Psychological Medicine, 36(4): 441e454.
A study involving 159 older adults (average age 76) has confirmed that the amount of brain tissue in specific regions is a predictor of Alzheimer’s disease development. Of the 159 people, 19 were classified as at high risk on the basis of the smaller size of nine small regions previously shown to be vulnerable to Alzheimer's), and 24 as low risk. The regions, in order of importance, are the medial temporal, inferior temporal, temporal pole, angular gyrus, superior parietal, superior frontal, inferior frontal cortex, supramarginal gyrus, precuneus.
There was no difference between the three risk groups at the beginning of the study on global cognitive measures (MMSE; Alzheimer’s Disease Assessment Scale—cognitive subscale; Clinical Dementia Rating—sum of boxes), or in episodic memory. The high-risk group did perform significantly more slowly on the Trail-making test part B, with similar trends on the Digit Symbol and Verbal Fluency tests.
After three years, 125 participants were re-tested. Nine met the criteria for cognitive decline. Of these, 21% were from the small high-risk group (3/14) and 7% from the much larger average-risk group (6/90). None were from the low-risk group.
The results were even more marked when less stringent criteria were used. On the basis of an increase on the Clinical Dementia Rating, 28.5% of the high-risk group and 9.7% of the average-risk group showed decline. On the basis of declining at least one standard deviation on any one of the three neuropsychological tests, half the high-risk group, 35% of the average risk group, and 14% (3/21) of the low-risk group showed decline. (The composite criteria required both of these criteria.)
Analysis estimated that every standard deviation of cortical thinning (reduced brain tissue) was associated with a nearly tripled risk of cognitive decline.
The 84 individuals for whom amyloid-beta levels in the cerebrospinal fluid were available also revealed that 60% of the high-risk group had levels consistent with the presence of Alzheimer's pathology, compared to 36% of those at average risk and 19% of those at low risk.
The findings extend and confirm the evidence that brain atrophy in specific regions is a biomarker for developing Alzheimer’s.
 Dickerson, B. C., & Wolk D. A.
(2012). MRI cortical thickness biomarker predicts AD-like CSF and cognitive decline in normal adults.
Neurology. 78(2), 84 - 90.
Dickerson BC, Bakkour A, Salat DH, et al. 2009. The cortical signature of Alzheimer’s disease: regionally specific cortical thinning relates to symptom severity in very mild to mild AD dementia and is detectable in asymptomatic amyloidpositive individuals. Cereb Cortex;19:497–510.
More than half of HIV patients experience memory problems and other cognitive impairments as they age. Now analysis of biomarkers in the cerebrospinal fluid have demonstrated how HIV-related cognitive impairment is like Alzheimer's-related dementia, and how it is different. The comparison of 49 HIV patients with cognitive impairments (average age 48), 21 HIV patients with normal cognitive function (average age 43), 68 patients with mild Alzheimer's (average age 74) and 50 normal, healthy controls (average age 50), found similarly low levels of amyloid beta in those HIV patients with cognitive impairments and those with Alzheimer’s — surprising researchers, and confirming an earlier study. Unlike the HIV patients however, those with mild Alzheimer's had significantly higher levels of tau.
 Clifford, D. B., Fagan A. M., Holtzman D. M., Morris J. C., Teshome M., Shah A. R., et al.
(2009). CSF biomarkers of Alzheimer disease in HIV-associated neurologic disease.
Neurology. WNL.0b013e3181c5b445 - WNL.0b013e3181c5b445.
A study involving 40 individuals with HIV, 38 with chronic alcoholism, 47 with both HIV and chronic alcoholism, and 39 controls, has found that although those with only one of these disorders mostly performed at levels comparable to controls on episodic and working memory tasks, those who were both positive for HIV and had a history of chronic heavy drinking were impaired on tests of immediate episodic memory (but not working memory) — meaning that they have trouble encoding new information for long-term memory. The finding is consistent with the fact that the mediotemporal lobe is affected early by both these conditions. Heavy drinking is very common among those infected with HIV.
 Fama, R., Rosenbloom M. J., Nichols N. B., Pfefferbaum A., & Sullivan E. V.
(2009). Working and episodic memory in HIV infection, alcoholism, and their comorbidity: baseline and 1-year follow-up examinations.
Alcoholism, Clinical and Experimental Research. 33(10), 1815 - 1824.
A compound derived from green tea greatly reduced the neurotoxicity of proteins secreted by the human immunodeficiency virus, suggesting a new approach to the prevention and treatment of HIV-associated dementia.
Brian Giunta reported the findings May 1 at Experimental Biology 2007 in Washington, DC.
Cognitive impairment in people with AIDS is caused when the HIV virus attacks the brain and can be a complicated syndrome resulting in deficits in mood, behavior, motor coordination and thought processes. While the incidence of severe dementia in people with AIDS has decreased significantly, a greater number of people are living with a milder form of cognitive impairment. A study of 54 participants with AIDS and 23 HIV-negative control subjects has found that cognitive impairment in people with AIDS exists in two forms -- one mild, another severe -- each affecting different areas of the brain. Of the 54 participants with AIDS, 17 demonstrated some level of mental impairment. The mild impairment group only showed problems in the area of psychomotor speed, and demonstrated atrophy in the frontal and anterior cingulate cortices. Those in the severe impairment group showed impairments in memory and visual-spatial processing as well as psychomotor speed, and had more significant atrophy that was located in the caudate and putamen.
The findings were presented April 5 at the American Academy of Neurology 58th Annual Meeting in San Diego.
A new imaging study has revealed a startlingly selective pattern of destruction inflicted by AIDS on brain regions. Only motor, language and sensory functions were affected. Also surprisingly, there was no difference in brain tissue loss between those taking antiretroviral drugs and those not. It appears that the blood barrier prevents these drugs entering the brain.
 Thompson, P. M., Dutton R. A., Hayashi K. M., Toga A. W., Lopez O. L., Aizenstein H. J., et al.
(2005). Thinning of the cerebral cortex visualized in HIV/AIDS reflects CD4+ T lymphocyte decline.
Proceedings of the National Academy of Sciences of the United States of America. 102(43), 15647 - 15652.
Treating HIV requires patients to rigorously follow a medication schedule; more than most diseases, the virus easily develops a resistance to the drugs if not taken reliably. Moreover, HIV can cause brain damage, making it more difficult for some patients to remember. A device known as Jerry (more formally, the Disease Management Assistance System) flashes a light and verbally tells the patient the exact dosage and medication to take at the correct time. Of the 58 patients in a recent study, those with Jerry took their medication 80% of the time, while those without did so only 65% of the time. The difference was only significant for those with memory impairment: of the 31 memory-impaired patients, those using Jerry had a 77% adherence rate, while those without Jerry had a 57% adherence rate.
 Andrade, A. S. A., McGruder H. F., Wu A. W., Celano S. A., Skolasky R. L., Selnes O. A., et al.
(2005). A programmable prompting device improves adherence to highly active antiretroviral therapy in HIV-infected subjects with memory impairment.
Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America. 41(6), 875 - 882.
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