treatment

Alzheimer's Treatment - Neurological & surgical interventions

Older news items (pre-2010) brought over from the old website

Gene Therapy

Targeting a key enzyme with gene therapy reversed course of Alzheimer's disease in mouse models

A study using genetically engineered mice has reversed the rats' memory loss by silencing a gene that helps produce amyloid plaques. The size and number of plaques were reduced by two-thirds within a month.

Singer, O. et al. 2005. Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model. Nature Neuroscience, 8, 1343-1349.

http://www.eurekalert.org/pub_releases/2005-09/si-tak092005.php

Gene therapy slows cognitive decline in trial

The first human clinical trial of gene therapy for Alzheimer’s, involving 8 volunteers, has found an increase in the brain’s use of glucose — a sign of brain activity — and a significant slowing of the patients’ rate of cognitive decline in the 6 patients who completed the procedure safely.

Tuszynski, M.H. et al. 2005. A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nature Medicine, 11(5), 551-555.

http://www.eurekalert.org/pub_releases/2005-04/uoc--acd041805.php

New gene therapy technique

A new technique using gene therapy to deliver nerve growth factor into regions of the brain where neurons are degenerating is being trialed in a two-year study. The technique, which requires neurosurgery to inject the drug precisely where it is required (the basal forebrain), uses a new drug called CERE-110. Extensive studies in several animal models, including primates, have showed that NGF gene delivery to the basal forebrain prevented the death of cholinergic neurons (which undergo severe degeneration and death in Alzheimer's disease patients).

http://www.eurekalert.org/pub_releases/2004-09/rpsl-seg092004.php

Preliminary results promising in Alzheimer's gene therapy trial

A small, preliminary study has had some success in delaying brain cell loss in early Alzheimer’s patients through the surgical placement of genetically modified tissue directly into their brains.

The study was reported on April 27 at the American Academy of Neurology meeting in San Francisco.

http://www.eurekalert.org/pub_releases/2004-04/uoc--pra042204.php

UCSD team performs first surgery in gene therapy protocol for Alzheimer's disease

In a groundbreaking procedure, physicians at the University of California, San Diego (UCSD) School of Medicine have surgically implanted genetically modified tissue into the brain of an Alzheimer's patient. This launches the first phase of an experimental gene therapy protocol for Alzheimer's disease. The therapy delivers a natural molecule called nerve growth factor (NGF) to the dying cells in the brain.
If the protocol is successful, implanted cells could begin to affect brain function in a month or two, but Tuszynski cautions that "it may take several years to test the procedure in a large enough number of patients to determine whether it will be useful therapy." The therapy is not expected to cure Alzheimer's disease, but it may restore some brain cells and alleviate symptoms such as short-term memory loss for several years.

Conner, J. M., Darracq, M. A., Roberts, J., & Tuszynski, M. H. (2001). Nontropic actions of neurotrophins: Subcortical nerve growth factor gene delivery reverses age-related degeneration of primate cortical cholinergic innervation. Proceedings of the National Academy of Sciences, 98(4), 1941–1946. doi:10.1073/pnas.98.4.1941

http://www.eurekalert.org/pub_releases/2001-04/UNKN-Utpf-0904101.php

CSF shunt

Draining toxins from cerebrospinal fluid stabilizes cognitive decline

The ever-slowing capacity to clear the build-up of such toxins as isoprostanes and misfolded proteins that accumulate in the brains of Alzheimer's disease patients causes the death of cells involved in memory and language. A preliminary study has shown that reducing the levels of isoprostanes by draining cerebral spinal fluid can stave off future reductions in cognitive abilities. Cognitive scores in the 8 patients receiving the treatment were stable after one year, while scores in those not receiving the treatment declined 20%. The next phase of the study involves nearly 100 patients.

Praticò, D., Yao, Y., Rokach, J., Mayo, M., Silverberg, G.G. & McGuire, D. 2004. Reduction of brain lipid peroxidation by CSF drainage in Alzheimer’s disease patients. Journal of Alzheimer's Disease, 6(4), 385-389.

http://www.eurekalert.org/pub_releases/2004-08/uopm-dti082004.php

Can Alzheimer's disease be slowed by shunting cerebrospinal fluid?

A pilot study has tested the hypothesis that improving cerebrospinal fluid (CSF) turnover will slow or stop the progression of dementia in people with Alzheimer's disease. CSF shunting for dementia, described in 1969, was largely abandoned due to mixed clinical results and an unacceptably high incidence of adverse events. However recent clinical studies in which CSF shunting was used to treat patients with symptomatic hydrocephalus demonstrated a coincidental lack of cognitive decline in patients who also had Alzheimer's dementia. A pilot study has found Alzheimer's patients who were shunted experienced relative stability while the control group demonstrated a fairly robust decline in cognitive function over the 12 months of the study. A larger, multi-center, controlled clinical trial is now underway.

Silverberg, G.D., Levinthal, E., Sullivan, E.V., Bloch, D.A., Chang, S.D., Leverenz, J., Flitman, S., Winn, R., Marciano, F., Saul, T., Huhn, S., Mayo, M. & McGuire, D. 2002. Assessment of low-flow CSF drainage as a treatment for AD: Results of a randomized pilot study. Neurology, 59, 1139-1145.

http://www.eurekalert.org/pub_releases/2002-10/aaon-cad101502.php

Possible new surgical treatment

An 18-month, double-blind placebo study into a new surgical treatment for Alzheimer’s disease using a device called the COGNIShunt, is being undertaken by neurologists at Emory University. The shunt is designed to drain cerebrospinal fluid (CSF) from the skull and into the abdominal cavity. By reducing the build-up of CSF around the brain, doctors hope this device will help to stabilize the disease. In a pilot study of the COGNIShunt, the device was well tolerated by individuals with mild to moderate Alzheimer’s disease.

http://www.eurekalert.org/pub_releases/2002-03/euhs-esc032102.php

Animal studies

Neurogenesis improved in Alzheimer mice

Studies of adult neurogenesis in genetically engineered mice have revealed two main reasons why amyloid-beta peptides and apolipoprotein E4 impair neurogenesis, and identified drug treatments that can fix it. The findings point to a deficit in GABAergic neurotransmission or an imbalance between GABAergic and glutamatergic neurotransmission as an important contributor to impaired neurogenesis in Alzheimer’s. While stem cell therapy for Alzheimer’s is still a long way off, these findings are a big step toward that goal.

Gang Li et al. 2009. GABAergic Interneuron Dysfunction Impairs Hippocampal Neurogenesis in Adult Apolipoprotein E4 Knockin Mice. Cell Stem Cell, 5 (6), 634-645. Binggui Sun et al. 2009. Imbalance between GABAergic and Glutamatergic Transmission Impairs Adult Neurogenesis in an Animal Model of Alzheimer's Disease. Cell Stem Cell, 5 (6), 624-633.

http://www.eurekalert.org/pub_releases/2009-12/gi-gsi113009.php

Neural stem cells offer potential treatment for Alzheimer's

Genetically engineered mice performed markedly better on memory tests a month after neural stem cells were injected into their Alzheimer-like brains. The stem cells secreted a protein that created more neural connections, improving cognitive function. Surprisingly, only 6% of the stem cells became neurons (most became ‘support cells’: astrocytes and oligodendrocytes). The benefit of stem cells seemed rather to lie in their secretion of BDNF, which encouraged the formation of new synapses. The direct injection of BDNF also had cognitive benefit, but not as much as with the neural stem cells, which provided a more long-term and consistent supply of the protein.

Norton, M.C. et al. 2009. Caregiver–Recipient Closeness and Symptom Progression in Alzheimer Disease. The Cache County Dementia Progression Study. The Journals of Gerontology Series B: Psychological Sciences and Social Sciences, Advance Access published on June 29, 2009. Full text available at http://www.pnas.org/content/106/32/13594.abstract

http://www.eurekalert.org/pub_releases/2009-07/uoc--nsc072009.php

Growth factor protects key brain cells in Alzheimer's models

In a series of cell culture and animal studies, involving genetically engineered mice, rats, and rhesus monkeys, injections of brain-derived neurotrophic factor (BDNF) resulted in significant improvement in brain functioning and on learning and memory tests. The growth factor, important for neurogenesis, is normally produced in the entorhinal cortex, an area damaged early in Alzheimer’s disease.

Nagahara, A.H. et al. 2009. Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease. Nature Medicine, 15, 331–337.

http://www.eurekalert.org/pub_releases/2009-02/uoc--gfp020309.php

Inhibitor of amyloid-beta clearing enzyme found

A new way of destroying amyloid-beta proteins has been found. Following previous research showing that the enzyme cathepsin B destroys the protein, scientists have now succeeded in increasing the activity of the enzyme by reducing the activity of the protease inhibitors cystatin C, the enzyme’s natural inhibitor. In mice, this had the effect of improving memory and extending life.

Sun, B. et al. 2008. Cystatin C-Cathepsin B Axis Regulates Amyloid Beta Levels and Associated Neuronal Deficits in an Animal Model of Alzheimer's Disease. Neuron, 60 (2), 247-257.

http://www.eurekalert.org/pub_releases/2008-10/gi-gsf102008.php

New way to target Alzheimer's disease

In a series of studies in transgenic mice, a synthetic peptide designed to block the interaction between apolipoprotein E and amyloid-beta protein reduced the aggregation of toxic amyloid protein in the brain by around 50%. The treated mice showed no memory decline.

Sadowski, M.J. et al. 2006. Blocking the apolipoprotein E/amyloid- interaction as a potential therapeutic approach for Alzheimer's disease. Proceedings of the National Academy of Sciences, 103, 18787-18792. The full text is available at http://www.pnas.org/cgi/content/full/103/49/18787

http://www.eurekalert.org/pub_releases/2006-12/nyum-sda120406.php

Androgen therapy may slow progress of Alzheimer's disease

Recent studies have suggested a link between testosterone loss in men and Alzheimer’s. A new study has now found a correlation between low testosterone and elevated beta-amyloid, providing more support that testosterone depletion in aging men increases the risk of Alzheimer’s. Testosterone belongs to a group of steroid hormones called androgens. The mouse study found that androgen therapy was successful in preventing beta-amyloid accumulation and cognitive decline in castrated mice.

Rosario, E.R. et al. 2006. Androgens Regulate the Development of Neuropathology in a Triple Transgenic Mouse Model of Alzheimer's Disease. Journal of Neuroscience, 26, 13384-13389.

http://www.eurekalert.org/pub_releases/2006-12/sfn-tm121906.php

Insulin receptor stops progression of Alzheimer's

Following previous research suggesting Alzheimer's might be a brain-specific neuroendocrine disorder, or a Type 3 diabetes, a new study has found that stimulation of a receptor in the brain that controls insulin responses prevents several components of neurodegeneration and preserves learning and memory in rats with induced Alzheimer's disease, raising the possibility that patients in the very early stages of Alzheimer’s might be treatable.

de la Monte, S.M. et al. 2006. Therapeutic rescue of neurodegeneration in experimental type 3 diabetes: relevance to Alzheimer’s disease. Journal of Alzheimer's Disease, 10 (1), 89-109.

http://www.eurekalert.org/pub_releases/2006-09/l-irs092106.php

Brain enzyme treatment for Alzheimer's

In a new approach to treating Alzheimer’s, increasing brain levels of ubiquitin C-terminal hydrolase L1 (Uch-L1) — an enzyme that helps neurons rid themselves of excess or aberrant proteins — has restored a great deal of brain activity to mice with Alzheimer's symptoms. The enzyme Uch-L1 is part of a network that controls a memory molecule called CREB, which is inhibited by amyloid beta proteins in people with Alzheimer's. Uch-L1 is found at reduced levels in the Alzheimer's brain. As well as improving memory in genetically engineered mice, treatments that restored Uch-L1 levels corrected deficits in nerve transmission both in brain slices treated with amyloid-beta and in slices taken from transgenic mice.

Gong, B. et al. 2006. Ubiquitin Hydrolase Uch-L1 Rescues B-Amyloid-Induced Decreases in Synaptic Function and Contextual Memory. Cell, 126, 775–788.

http://www.eurekalert.org/pub_releases/2006-08/cp-bet082106.php
http://www.eurekalert.org/pub_releases/2006-08/cumc-crr082206.php

Why chances of Alzheimer's increase with age

Experiments with roundworms have revealed two important proteins that help slow down the accumulation of amyloid-beta. HSF-1 breaks apart amyloid and disposes of it — but aging slows HSF-1, so it can't keep up. DAF-16 helps it out, by clumping extra amyloid together in a way that makes it less toxic. The finding supports recent research indicating amyloid clumps, or plaques, are not the main problem, rather, smaller amyloid tendrils inside cells are. The study also explains why aging increases the likelihood of Alzheimer’s. Most importantly of all, it suggests a new approach to treating Alzheimer’s.

Cohen, E. et al. 2006. Opposing Activities Protect Against Age-Onset Proteotoxicity. Science, 313 (5793), 1604–1610.

http://www.msnbc.msn.com/id/14290153/
http://www.boston.com/news/nation/articles/2006/08/11/scientists_find_natural_alzheimers_controls/

Potential new treatment strategy for Alzheimer's

A study has identified several new compounds that could play a role in preventing or treating Alzheimer's disease and other degenerative conditions of the nervous system. In culture, these compounds bind with a receptor called p75NTR; a receptor that in the body binds neurotrophins. There is some evidence that in Alzheimer's, some of the neurons that die express the p75NTR binding site, indicating they may be dying because neurotrophins are binding to them. Because the new compounds bind with p75NTR in place of neurotrophins, they may provide a means of preventing damage that neurotrophins would otherwise be causing. The compounds were also found to inhibit the death of oligodendrocytes.

Massa, S.M. et al. 2006. Small, Nonpeptide p75NTR Ligands Induce Survival Signaling and Inhibit proNGF-Induced Death. Journal of Neuroscience, 26, 5288-5300.

http://www.eurekalert.org/pub_releases/2006-05/uoc--pnt051706.php

Memory loss in genetically engineered mice reversed

Mice were genetically engineered to develop dementia; the transgene was designed to be able to be turned off. The researchers expected that when the transgene expressing the dementia was turned off, memory loss would stop. Instead, they were surprised to find the loss was reversed; the mice regained their memory. A further surprise occurred when it was found that the neurofibrillary tangles, thought to be one of the causes of dementia, remained, and even increased, suggesting that the tangles are not a cause of dementia.

SantaCruz, K. et al. 2005. Tau Suppression in a Neurodegenerative Mouse Model Improves Memory Function, Science, 309 (5733), 476-481.

http://www.eurekalert.org/pub_releases/2005-07/uom-uom071105.php

Inhibiting Apolipoprotein E possible means of therapeutic intervention

It has been known that the inflammatory protein ApoE can speed the buildup in the brain of amyloid plaques,but the mechanism has not been known. A mouse study found ApoE is responsible for converting harmless amyloid-beta into the toxic fibrous deposits known as filamentous amyloid. This process is needed to damage nerve cells in parts of the brain controlling memory and cognition. Mice with Alzheimer's disease showed memory deficits only when the ApoE gene was present. The study suggests that preventing ApoE from acting upon amyloid-beta may prove to be an effective means of therapeutic intervention.

Costa, D.A., Nilsson, L.N.G., Bales, K.R., Paul, S.M. & Potter, H. 2004. Apolipoprotein E is required for the formation of filamentous amyloid but not for amorphous AB deposition, in an Aâ PP/PS double transgenic mouse model of Alzheimer's disease. Journal of Alzheimer's Disease, 6, 509–514.

Nilsson, L.N.G., Arendash, G.W., Leighty, R.E., Costa, D.A., Garcia, M.F., Cracciola, J.R., Rojiani, A., Wu, X., Bales, K.R., Paul, S.M. & Potter, H. 2004. Cognitive impairment in PDAPP mice depends on ApoE and ACT-catalyzed amyloid. Neurobiology of Aging, 25 (9), 1153-1167.

http://www.eurekalert.org/pub_releases/2004-10/uosf-rur102904.php

Researchers identify brain protein that halts progression of Alzheimer's

Researchers have identified a protein in the brain, "transthyretin," that halts the progression of Alzheimer's disease in human brain tissue by blocking beta-amyloid.

The findings were presented on October 26 at the 34th annual meeting of the Society for Neuroscience in San Diego, Calif.

http://www.eurekalert.org/pub_releases/2004-10/nioe-rib102504.php

Early clinical treatment can halt progression of Alzheimer's disease

A study using genetically engineered mice has provided evidence that early clinical treatment of brain lesions (by injecting anti-beta-amyloid antibodies into the hippocampus) can halt the progression of Alzheimer's disease. The clearance of amyloid plaques led to the clearance of the lesions caused by neurofibrillary tangles. The effect on neurofibrillary tangles only occurs, however, if done at a particular stage of the tangle’s growth — the earlier the treatment begins, therefore, the better the chance of success. The demonstration that early treatment of amyloid plaques stops the progression of Alzheimer’s provides support for the controversial theory that the accumulation of amyloid plaques is the initiating trigger of the disease process.

Oddo, S., Billings, L., Kesslak, P., Cribbs, D.H. & LaFerla, F.M. 2004. Aβ Immunotherapy Leads to Clearance of Early, but Not Late, Hyperphosphorylated Tau Aggregates via the Proteasome. Neuron, 43, 321-332.

http://www.eurekalert.org/pub_releases/2004-08/uoc--ect072804.php

Buildup of amyloid plaques linked to gene inhibition

Examination of genetically engineered mice and of brain tissue from deceased Alzheimer's patients has found that the buildup of amyloid plaques in the brain dramatically inhibits six genes known to be important for the formation of new memories. The finding suggests a new approach to the treatment of Alzheimer’s disease, combining amyloid-lowering treatment with other strategies designed to block the effect of amyloid on these genes.

Dickey, C.A. et al. 2003. Selectively Reduced Expression of Synaptic Plasticity-Related Genes in Amyloid Precursor Protein + Presenilin-1 Transgenic Mice. Journal of Neuroscience, 23, 5219-5226.

http://www.eurekalert.org/pub_releases/2003-06/uosf-sla062503.php

A new approach to slowing the progression of Alzheimer’s

Researchers have discovered the molecules that play a critical role in making the brain think it is under attack from the amyloid plaques characteristic of Alzheimer’s disease. Microglial cells detect beta amyloid plaques and gear up to fight them as foreign invaders. However, for some unknown reason, they don’t follow through on the attack, but remain inflamed. It is this inflammation that causes a lot of the problem. Research has now shown that the microglial cells at least four different receptor proteins to bind to the amyloid. Each one of these receptor proteins act together at the same time to drive the inflammation. This discovery suggests a new approach to treating Alzheimer’s — finding a means to block these receptors.

Bamberger, M.E., Harris, M.E., McDonald, D.R., Husemann, J. & Landreth, G.E. 2003. A Cell Surface Receptor Complex for Fibrillar b-Amyloid Mediates Microglial Activation. Journal of Neuroscience, 23, 2665-2674.

http://www.eurekalert.org/pub_releases/2003-04/cwru-mti042903.php

Gene transfer reduces levels of key Alzheimer's disease protein

An animal study has found that a molecule that naturally degrades of the protein beta-amyloid (the substance in the amyloid plaques indicative of Alzheimer’s) appears to reduce the levels of that protein by nearly 50% when delivered by gene therapy.

Marr, R.A., Rockenstein, E., Mukherjee, A., Kindy, M.S., Hersh, L.B., Gage, F.H., Verma, I.M. & Masliah, E. 2003. Neprilysin Gene Transfer Reduces Human Amyloid Pathology in Transgenic Mice. Journal of Neuroscience, 23, 1992-1996.

http://www.eurekalert.org/pub_releases/2003-03/si-gtr032003.php

Growth factor creates new neurons; may aid treatment of neurological diseases

In a series of studies, a growth factor (BDNF) was introduced into the adult rat brain, and was found to produce new neurons in various brain regions. BDNF is reduced in parts of the brain of those with Huntington’s disease and Alzheimer’s disease. These studies indicate that supplementing the adult brain with BDNF not only supports neurons in those brains, but also induces new neurons from precursor cells.

Pencea, V., Bingaman, K. D., Wiegand, S. J., & Luskin, M. B. (2001). Infusion of Brain-Derived Neurotrophic Factor into the Lateral Ventricle of the Adult Rat Leads to New Neurons in the Parenchyma of the Striatum, Septum, Thalamus, and Hypothalamus. The Journal of Neuroscience, 21(17), 6706–6717. Retrieved from http://www.jneurosci.org/content/21/17/6706

Benraiss, A., Chmielnicki, E., Lerner, K., Roh, D., & Goldman, S. A. (2001). Adenoviral Brain-Derived Neurotrophic Factor Induces Both Neostriatal and Olfactory Neuronal Recruitment from Endogenous Progenitor Cells in the Adult Forebrain. The Journal of Neuroscience, 21(17), 6718–6731. Retrieved from http://www.jneurosci.org/content/21/17/6718

http://www.eurekalert.org/pub_releases/2001-08/sfn-nnm083101.php

Transplanted human neural stem cells improve memory in rats

Laboratory-grown human neural stem cells, the building blocks of the brain, were successfully transplanted for the first time into the brains of aged rats and dramatically improved the animals' cognitive function. The results of the study could lay the foundation for new treatments in diseases such as Alzheimer's and Parkinson's.
Neural cell transplant studies recently suffered a setback when transplanted fetal cells worsened symptoms in Parkinson's patients. However, such fetal cells are already differentiated. Laboratory-grown stem cells are not differentiated, allowing the host brain to take over, dictating where the stem cells should migrate and what types of cells they should become. As a result, the transplanted cells became functionally integrated into the neuronal circuitry of the host animal. Postmortem examination of the rats' brains demonstrated that the transplanted human brain cells had not only differentiated and were thriving in the new environment, but that the rats' own neuronal fibers had grown dramatically in areas associated with spatial memory.

Qu,T, Brannen, C.L., Kim, H.M., & Sugay, K. (n.d.). Human neural stem cells improve cognitive function of aged brain. Retrieved 27 April 2013, from http://journals.lww.com/neuroreport/Fulltext/2001/05080/Human_neural_ste...

http://www.eurekalert.org/pub_releases/2001-04/UoIa-Thns-2304101.php

tags development: 

tags problems: 

Popular cognitive test for Alzheimer’s insufficiently sensitive

January, 2013

The most common cognitive test used in clinical trials for Alzheimer’s treatments has been shown to have significant flaws that underestimate cognitive change.

New research suggests that reliance on the standard test Alzheimer's Disease Assessment Scale—Cognitive Behavior Section (ADAS-Cog) to measure cognitive changes in Alzheimer’s patients is a bad idea. The test is the most widely used measure of cognitive performance in clinical trials.

Using a sophisticated method of analysis ("Rasch analysis"), analysis of ADAS-Cog data from the AD Neuroimaging Initiative (675 measurements from people with mild Alzheimer's disease, across four time points over two years) revealed that although final patient score seemed reasonable, at the component level, a ceiling effect was revealed for eight out of the 11 parts of the ADAS-Cog for many patients (32-83%).

Additionally, for six components (commands, constructional praxis, naming objects and fingers, ideational praxis, remembering test instructions, spoken language), the thresholds (points of transition between response categories) were not ordered sequentially. The upshot of this is that, for these components, a higher score did not in fact confirm more cognitive impairment.

The ADAS-Cog has 11 component parts including memory tests, language skills, naming objects and responding to commands. Patients get a score for each section resulting in a single overall figure; different sections have different score ranges. A low total score signals better cognitive performance; total score range is 0-70, with 70 being the worst.

It seems clear from this that the test seriously underestimates cognitive differences between people and changes over time. Given that this is the most common cognitive test used in clinical trials, we have to consider whether these flaws account for the failure of so many drug trials to find significant benefits.

Among the recommended ways to improve the ADAS-Cognitive (including the need to clearly define what is meant by cognitive performance!), the researchers suggest that a number of the components should be made more difficult, and that the scoring function of those six components needs to be investigated.

Reference: 

Source: 

Topics: 

tags development: 

tags problems: 

Dopamine decline underlies episodic memory decline in old age

December, 2012

Findings supporting dopamine’s role in long-term episodic memory point to a decline in dopamine levels as part of the reason for cognitive decline in old age, and perhaps in Alzheimer’s.

The neurotransmitter dopamine is found throughout the brain and has been implicated in a number of cognitive processes, including memory. It is well-known, of course, that Parkinson's disease is characterized by low levels of dopamine, and is treated by raising dopamine levels.

A new study of older adults has now demonstrated the effect of dopamine on episodic memory. In the study, participants (aged 65-75) were shown black and white photos of indoor scenes and landscapes. The subsequent recognition test presented them with these photos mixed in with new ones, and required them to note which photos they had seen before. Half of the participants were first given Levodopa (‘L-dopa’), and half a placebo.

Recognition tests were given two and six hours after being shown the photos. There was no difference between the groups at the two-hour test, but at the six-hour test, those given L-dopa recognized up to 20% more photos than controls.

The failure to find a difference at the two-hour test was expected, if dopamine’s role is to help strengthen the memory code for long-term storage, which occurs after 4-6 hours.

Individual differences indicated that the ratio between the amount of Levodopa taken and body weight is key for an optimally effective dose.

The findings therefore suggest that at least part of the reason for the decline in episodic memory typically seen in older adults is caused by declining levels of dopamine.

Given that episodic memory is one of the first and greatest types of memory hit by Alzheimer’s, this finding also has implications for Alzheimer’s treatment.

Caffeine improves recognition of positive words

Another recent study also demonstrates, rather more obliquely, the benefits of dopamine. In this study, 200 mg of caffeine (equivalent to 2-3 cups of coffee), taken 30 minutes earlier by healthy young adults, was found to improve recognition of positive words, but had no effect on the processing of emotionally neutral or negative words. Positive words are consistently processed faster and more accurately than negative and neutral words.

Because caffeine is linked to an increase in dopamine transmission (an indirect effect, stemming from caffeine’s inhibitory effect on adenosine receptors), the researchers suggest that this effect of caffeine on positive words demonstrates that the processing advantage enjoyed by positive words is driven by the involvement of the dopaminergic system.

Reference: 

Source: 

Topics: 

tags: 

tags development: 

tags memworks: 

tags problems: 

Timing of estrogen therapy is crucial

October, 2011

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

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

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

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

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

Reference: 

Source: 

Topics: 

tags development: 

tags lifestyle: 

tags problems: 

Possible treatment for working memory decline with age

September, 2011

A study has successfully countered reduced activity in the prefrontal cortex seen in older monkeys. Clinical trials are now investigating whether the drug can improve working memory in older humans.

A study comparing activity in the dorsolateral prefrontal cortex in young, middle-aged and aged macaque monkeys as they performed a spatial working memory task has found that while neurons of the young monkeys maintained a high rate of firing during the task, neurons in older animals showed slower firing rates. The decline began in middle age.

Neuron activity was recorded in a particular area of the dorsolateral prefrontal cortex that is most important for visuospatial working memory. Some neurons only fired when the cue was presented (28 CUE cells), but most were active during the delay period as well as the cue and response periods (273 DELAY neurons). Persistent firing during the delay period is of particular interest, as it is required to maintain information in working memory. Many DELAY neurons increased their activity when the preferred spatial location was being remembered.

While the activity of the CUE cells was unaffected by age, that of DELAY cells was significantly reduced. This was true both of spontaneous activity and task-related activity. Moreover, the reduction was greatest during the cue and delay periods for the preferred direction, meaning that the effect of age was to reduce the ability to distinguish preferred and non-preferred directions.

It appeared that the aging prefrontal cortex was accumulating excessive levels of an important signaling molecule called cAMP. When cAMP was inhibited or cAMP-sensitive ion channels were blocked, firing rates rose to more youthful levels. On the other hand, when cAMP was stimulated, aged neurons reduced their activity even more.

The findings are consistent with rat research that has found two of the agents used — guanfacine and Rp-cAMPS — can improve working memory in aged rats. Guanfacine is a medication that is already approved for treating hypertension in adults and prefrontal deficits in children. A clinical trial testing guanfacine's ability to improve working memory and executive functions in elderly subjects who do not have dementia is now taking place.

Reference: 

[2349] Wang, M., Gamo N. J., Yang Y., Jin L. E., Wang X-J., Laubach M., et al.
(2011).  Neuronal basis of age-related working memory decline.
Nature. advance online publication,

Source: 

Topics: 

tags development: 

tags memworks: 

tags problems: 

Why it gets harder to remember as we get older

June, 2011

A new study finds that older adults have more difficulty in recognizing new information as ‘new’, and this is linked to degradation of the path leading into the hippocampus.

As we get older, when we suffer memory problems, we often laughingly talk about our brain being ‘full up’, with no room for more information. A new study suggests that in some sense (but not the direct one!) that’s true.

To make new memories, we need to recognize that they are new memories. That means we need to be able to distinguish between events, or objects, or people. We need to distinguish between them and representations already in our database.

We are all familiar with the experience of wondering if we’ve done something. Is it that we remember ourselves doing it today, or are we remembering a previous occasion? We go looking for the car in the wrong place because the memory of an earlier occasion has taken precedence over today’s event. As we age, we do get much more of this interference from older memories.

In a new study, the brains of 40 college students and older adults (60-80) were scanned while they viewed pictures of everyday objects and classified them as either "indoor" or "outdoor." Some of the pictures were similar but not identical, and others were very different. It was found that while the hippocampus of young students treated all the similar pictures as new, the hippocampus of older adults had more difficulty with this, requiring much more distinctiveness for a picture to be classified as new.

Later, the participants were presented with completely new pictures to classify, and then, only a few minutes later, shown another set of pictures and asked whether each item was "old," "new" or "similar." Older adults tended to have fewer 'similar' responses and more 'old' responses instead, indicating that they could not distinguish between similar items.

The inability to recognize information as "similar" to something seen recently is associated with “representational rigidity” in two areas of the hippocampus: the dentate gyrus and CA3 region. The brain scans from this study confirm this, and find that this rigidity is associated with changes in the dendrites of neurons in the dentate/CA3 areas, and impaired integrity of the perforant pathway — the main input path into the hippocampus, from the entorhinal cortex. The more degraded the pathway, the less likely the hippocampus is to store similar memories as distinct from old memories.

Apart from helping us understand the mechanisms of age-related cognitive decline, the findings also have implications for the treatment of Alzheimer’s. The hippocampus is one of the first brain regions to be affected by the disease. The researchers plan to conduct clinical trials in early Alzheimer's disease patients to investigate the effect of a drug on hippocampal function and pathway integrity.

Reference: 

Source: 

Topics: 

tags development: 

tags memworks: 

tags problems: 

Tobacco-derived compound prevents memory loss in Alzheimer's mice

June, 2011

A mouse study has found that a compound derived from tobacco reduced plaques associated with dementia and prevented memory loss.

Some epidemiological studies have showed that people who smoke tend to have lower incidences of Parkinson's disease and Alzheimer's disease; this has been widely attributed to nicotine. However, nicotine's harmful effects make it a poor drug candidate.

Cotinine, a byproduct of nicotine metabolism, is nontoxic and longer lasting than nicotine.

In the study, genetically engineered 2-month-old mice were given cotinine daily for five months. When tested, those treated with cotinine performed at the same level as normal mice on spatial memory tests, and showed a 26% reduction in deposits of amyloid plaques, compared to the genetically engineered mice who had not received the treatment. Cotinine also inhibited the accumulation of the amyloid peptide oligomers, and stimulated the signaling factor Akt, which promotes the survival of neurons and enhances attention and memory.

The researchers are hoping to carry out a pilot clinical trial to investigate cotinine's effectiveness in preventing progression to Alzheimer's dementia in patients with mild cognitive impairment.

Reference: 

Echeverria, V. et al. In press. Cotinine Reduces Amyloid-β Aggregation and Improves Memory in Alzheimer's Disease Mice. Journal of Alzheimer's Disease, 24 (4).

Source: 

Topics: 

tags development: 

tags problems: 

Deep Brain Stimulation shows promise for patients with Alzheimer's

September, 2010

A safety trial has shown that Deep Brain Stimulation is safe for those with mild Alzheimer’s, and may slow cognitive decline.

A pilot study involving six patients with mild Alzheimer’s has shown using Deep Brain Stimulation (DBS) is safe and may help improve memory, or at least slow decline. Patients received continuous stimulation for 12 months, between 2005 and 2008. Impaired glucose utilization in the temporal and parietal lobes was dramatically reversed early in the treatment, and maintained after the year of continuous stimulation. Performance on cognitive tests showed possible improvement and/or slowing in the rate of cognitive decline at 6 and 12 months in three of the six patients.

The principal aim of this pilot study was to assess the safety of the procedure, and it is now hoped to move on to a larger study to assess its effectiveness. Anyone interested in more information about participating in the next phase should visit: http://www.uhn.on.ca/Focus_of_Care/KNC/Functional_Neurosurgery/research.asp.

Reference: 

Source: 

Topics: 

tags: 

tags development: 

tags problems: 

Special care plan does not slow decline in patients with Alzheimer's

August, 2010

A large French study has found no evidence that special care plans for dementia patients improve the outcomes.

A study involving over 1100 patients with mild to moderate Alzheimer's disease at 50 French clinics has revealed that receiving a comprehensive care plan involving regular 6-monthly assessments (with standardised guidelines for the management of problems) produced no benefits compared to receiving the usual care (an annual consultation). After two years, there was no significant difference in functional decline between the two groups, and no difference in the risk of being admitted to an institution or death. While this argues against guideline-based interventions for dementia care (widely recommended), it may be that the treatment received by both groups was superior to that received by those who do not attend a specialized memory clinic. It remains to be seen whether the findings would be different for patients being treated in general practice.

It should also be noted that this study only measured the effects on daily activities, institutionalization, and death. A number of studies have found improvements in specific behaviors (eg, reduced behavioral problems, reduced agitation, or improved quality of life) as a result of particular care programs. The fact that, in this case, interventions were more frequent early in the study compared to later, suggests that the care plan may not have been all that easy to implement.

Reference: 

Source: 

Topics: 

tags development: 

tags problems: 

Pages

Subscribe to RSS - treatment
Error | About memory

Error

The website encountered an unexpected error. Please try again later.