Memantine

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.

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.

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.

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.

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.

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.

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….

A study involving outpatients with early stage Alzheimer’s found that their performance on some computerized tests of executive function and visual attention, including a simulated driving task, improved significantly after three months of taking cholinesterase inhibitors. Specifically, the drug treatment was associated with an improved ability to accurately maintain lane position during the simulated driving task; to accurately and quickly detect a target in a visual search task; to more quickly complete computerized mazes.

A pilot study involving 21 institutionalized individuals with moderate-to-severe Alzheimer’s found that, although drinking two 4-oz glasses of apple juice daily for a month produced no change in the Dementia Rating Scale or in the Activities of Daily Living measure, there was a significant (27%) improvement in behavioral and psychotic symptoms. The largest changes occurred in anxiety, agitation, and delusion.

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.

Although research has so far been confined to mouse studies, researchers are optimistic about the promise of histone deacetylase inhibitors in reversing age-related memory loss — both normal decline, and the far more dramatic loss produced by Alzheimer’s. The latest study reveals that memory impairment in the aging mouse is associated with altered hippocampal chromatin plasticity, specifically with the failure of histone H4 lysine 12 acetylation, leading to a failure to initiate the gene expression program associated with memory consolidation. Restoring this acetylation leads to the recovery of cognitive abilities.

A special supplement in the Journal of Alzheimer's Disease focuses on the effects of caffeine on dementia and age-related cognitive decline. Here are the highlights:

A mouse study has found memory restoration and lower levels of amyloid-beta in Alzheimer’s mice following only 1-2 months of caffeine treatment. The researchers talk of “ a surprising ability of moderate caffeine intake to protect against or treat AD”, and define moderate intake as around 5 cups of coffee a day(!).

A review of studies into the relation between caffeine intake, diabetes, cognition and dementia, concludes that indications that coffee/caffeine consumption is associated with a decreased risk of Type 2 diabetes and possibly also with a decreased dementia risk, cannot yet be confirmed with any certainty.

A study involving 351 older adults without dementia found the association between caffeine intake and cognitive performance disappeared once socioeconomic status was taken into account.

A study involving 641 older adults found caffeine consumption was significantly associated with less cognitive decline for women only. Supporting this, white matter lesions were significantly fewer in women consuming more than 3 units of caffeine per day (after adjustment for age) than in women consuming less.

A Portuguese study involving 648 older adults found that caffeine intake was associated with a lower risk of cognitive decline in women, but not significantly in men.

A review of published studies examining the relation between caffeine intake and cognitive decline or dementia shows a trend towards a protective effect of caffeine, but because of the limited number of epidemiological studies, and the methodological differences between them, is unable to come up with a definitive conclusion.

A review of published epidemiological studies looking at the association between caffeine intake and Parkinson’s Disease confirms that higher caffeine intake is associated with a lower risk of developing Parkinson’s Disease (though this association may be stronger for men than women). Other studies provide evidence of caffeine’s potential in treatment, improving both the motor deficits and non-motor symptoms of Parkinson’s.

The Phase II clinical trial of a treatment using naturally occurring antibodies (IGIV) has achieved significantly lower rates of ventricular enlargement (6.7% vs 12.7% per year) and less whole-brain atrophy (1.6% vs 2.2% per year) than control subjects who initially received placebo. The trial ran for 18 months and involved 24 patients with mild to moderate Alzheimer's disease, of whom 16 received IGIV once or twice a month for the whole period, and 8 received a placebo for the first 6 months. Those who responded best to IGIV did not measurably decline over 18 months, and had an average rate of brain shrinkage and average rate of ventricular enlargement comparable to the rate previously reported in normal elderly individuals. Most tellingly, differences in rates were associated with dosage rates (there were four different regimens). A much larger trial is now being carried out.

The American Academy of Neurology has updated its guidelines on when people with dementia should stop driving. While the guidelines point out that this decision is a complex one that should be made by a doctor using the Clinical Dementia Rating scale, they also supported caregivers’ instincts, which have been found to often be correct. For caregivers and family members, the following warning signs are identified:

• Decreased miles being driven
• Collisions
• Moving violations
• Avoiding certain driving situations, such as driving at night or in the rain
• Aggressive or impulsive personality traits

However, the patient’s own self-rating, and a lack of situational avoidance, are not regarded as useful evidence.

A few months ago, I reported on an exciting finding that rapamycin, a drug currently used in transplant patients, improved memory in Alzheimer's mice. Now a different strain of mice (ones engineered to have defects in the genes that make amyloid precursor protein) has also shown improvements in learning and memory, correlated with less damage in brain tissue, after rapamycin treatment lowered levels of amyloid-beta-42. The mice given the drug performed at levels comparable with normal mice.

Rapamycin, a drug that keeps the immune system from attacking transplanted organs, was recently found to extend the life span of aged research mice. Now a study involving genetically engineered mice has found that 10 weeks of taking the drug improved learning and memory and reduced Alzheimer's-like damage in the brain.

A European trial involving 225 patients with mild Alzheimer's has found that those who drank Souvenaid (a cocktail of uridine, choline and the omega-3 fatty acid DHA, plus B vitamins, phosopholipids and antioxidants) for 12 weeks were more likely to improve their performance in a delayed verbal recall task. 40% of the Souvenaid group showed improved performance compared to 24% of the placebo group. Those with the mildest cases of Alzheimer’s showed the most improvement. There was no improvement on the more general ADAS-cog test. Three further clinical trials, one in the U.S. and two in Europe, are now underway.

I rarely report on drugs, but because I do have a number of early reports on the four drugs approved for use with Alzheimer’s, I wanted to provide this update.

The four drugs are donepezil, rivastigmine, galantamine and memantine. This review is said to be the first to rank their comparative safety and effectiveness. It used evidence from 142 clinical trials published between 1996 and 2015. The number of patients in each study ranged from 13 to 2,045, and the review evaluated a total of 33,889 patients.

Donepezil was the most effective medication for Alzheimer's dementia across all effectiveness outcomes, including cognition, behavior and overall health, according to the study. It was also the only cognitive enhancer that produced effects that could be observed clinically, not merely statistically.

However, patients who took donepezil were more likely to experience side effects including nausea, vomiting and diarrhea than those who received a placebo.

Previous research found that these drugs don’t improve cognition or function in people with MCI, and these patients experience significantly more nausea, diarrhea, vomiting and headaches.

https://www.eurekalert.org/pub_releases/2017-09/smh-srs092817.php

Memantine plus care program dramatically better at reducing Alzheimer's symptoms than drug alone

A small study found that combining a specific care management program with memantine multiplied the drug’s ability to improve daily function by about 7.5 times.

The Comprehensive, Individualized, Person-Centered Management program (CI-PCM) includes caregiver training, residence assessment, therapeutic home visits, and caregiver support groups.

In the 28-week, blinded, randomized controlled trial, 10 patient-caregiver groups enrolled in the CI-PCM were compared against 10 pairs receiving standard community care. All patients were taking memantine. Participants were assessed at the end of the trial using a recognized tool called Functional Assessment Staging (FAST), which measures losses in the ability of a person to independently carry out daily activities, such as dressing, bathing and toileting.

Caregiver training included "memory coaching" that teaches patients how to accomplish skills they lost.

The findings were presented July 16 at the Alzheimer's Association International Conference 2017 in London.

https://www.eurekalert.org/pub_releases/2017-07/nlmc-dcw071317.php