A study published this week in the Journal of Neuroscience shows that the compound epothilone D (EpoD) is effective in preventing further neurological damage and improving cognitive performance in a mouse model of Alzheimer’s disease (AD). The results establish how the drug might be used in early-stage AD patients.

…EpoD acts by the same microtubule-stabilizing mechanism as the FDA-approved cancer drug paclitaxel (Taxol™). These drugs prevent cancer cell proliferation by over-stabilizing specialized microtubules involved in the separation of chromosomes during the process of cell division. However, the Penn researchers previously demonstrated that EpoD, unlike paclitaxel, readily enters the brain and so may be useful for treating AD and related disorders.

After three months of receiving EpoD, additional tau clumps did not form in the brains of the aged AD mice, and nerve-cell function was increased compared to the AD mice that did not receive drug. What’s more, the EpoD-treated mice showed improvements in learning and memory. Importantly, the doses of EpoD that resulted in these benefits were much lower than had previously been used in Phase II clinical testing of EpoD in cancer patients. The investigators observed no side-effects — including the suppression of the immune system and peripheral nerve damage — in the transgenic mice that received EpoD. _UPennNews

Most approaches to treating Alzheimer’s dementia aim to either affect the levels of neurotransmitters in the brain — particularly acetylcholine — or to decrease accumulation of amyloid beta protein.

The idea of over-stabilising neurotubules to prevent tau tangles from forming in early stage Alzheimer’s is an intriguing approach, and dates to earlier studies attempting to discover the true etiological origins of Alzheimer’s. More from a 2011 study published in The Journal of Neuroscience:

Alzheimer’s disease (AD) pathology is characterized by senile plaques (SPs) and neurofibrillary tangles (NFTs) (Selkoe, 2001). SPs are extracellular deposits of amyloid-β (Aβ), a 3–4 kDa peptide derived from proteolytic cleavage of the amyloid precursor protein (APP) by β-site APP cleavage enzyme 1 (BACE) (Hussain et al., 1999; Sinha et al., 1999; Vassar et al., 1999; Yan et al., 1999) and the presenilin (PS)-containing γ-secretase complex (De Strooper et al., 1998; Wolfe et al., 1999). NFTs are intracellular accumulations of hyperphosphorylated tau (Lee et al., 2001). About 5% of AD cases are linked to pathogenic mutations in APP, PS1, or PS2 genes (Selkoe, 2001). Tau gene mutations are pathogenic for familial frontotemporal lobar degeneration characterized by tau pathology without SPs, indicating that tau abnormalities alone cause neurodegenerative disease (Lee et al., 2001). _Journal of Neuroscience 25 May 2011, 31(21): 7691-7699; doi: 10.1523/​JNEUROSCI.6637-10.2011

Note that researchers are still attempting to unravel the apparent multiple strings of causation involved in Alzheimer’s Disease (AD) and similar neurodegenerative diseases of the brain.

The new research involving microtubule stabilisation, was performed in transgenic mice, meaning that results in human populations using such treatments may be quite different. The fact that both amyloid placques and tau tangles are seen in pathological brain specimens from AD patients suggests that more than one treatment approach may ultimately be required for many, if not most AD sufferers.

Cross-posted from Al Fin blog

Al Fin Longevity

The ongoing study of current cognitive enhancers such as those in the table above, have given us scattered hints as to what future therapies might offer. Here is a short list of possible future targets for cognitive therapies:

Among targets under investigation, cholinergic receptors have received much attention with several nicotinic agonists (α7 and α4β2) actively in clinical trials for the treatment of AD, CIAS and attention deficit hyperactivity disorder (ADHD). Both glutamatergic and serotonergic (5-HT) agonists and antagonists have profound effects on neurotransmission and improve cognitive function in preclinical experiments with animals; some of these compounds are now in proof-of-concept studies in humans. Several histamine H3 receptor antagonists are in clinical development not only for cognitive enhancement, but also for the treatment of narcolepsy and cognitive deficits due to sleep deprivation because of their expression in brain sleep centers. Compounds that dampen inhibitory tone (e.g., GABAA α5 inverse agonists) or elevate excitatory tone (e.g., glycine transporter inhibitors) offer novel approaches for treating diseases such as schizophrenia, AD and Down syndrome. In addition to cell surface receptors, intracellular drug targets such as the phosphodiesterases (PDEs) are known to impact signaling pathways that affect long-term memory formation and working memory. Overall, there is a genuine need to treat cognitive deficits associated with many neuropsychiatric conditions as well as an increasingly aging population. _Source

It is important for us, at the outset, to take as realistic a viewpoint toward the possibility of meaningful cognitive enhancement as possible. The Likelihood of Cognitive Enhancement (Lynch et al 2011 PDF) is a useful introduction to many of the practical issues that need to be faced from the very beginning of this enterprise. Cognitive Enhacement: Promises and Perils (Hyman 2011 PDF) is a less technical introduction to the topic, perhaps more accessible to most laymen.

Cognitive Enhancement as a Pharmacotherapy Target for Stimulant Addiction (Sofuoglu 2010) looks at the use of cognitive enhancers as possible treatments for cocaine and methamphetamine addictions. Long term and heavy use of these drugs leads to cognitive deficits which make it even more difficult for a person to stop using these drugs and lead a “normal” life. The restoration of cognitive function is likely to provide a certain amount of “mental fortification” to allow at least some addicts to turn away from the dead end lifestyle. Similarly, restoration of cognitive function in persons suffering from age-related neurodegeneration is more likely to allow the person to participate in normal social interaction, and to undertake some level of responsibility, and perhaps productive activity.

Emerging Pharmacotherapies for Neurodevelopmental Disorders (Wetmore et Garner 2010) looks at the use of cognitive enhancers for persons who suffer from neurodevelopmental disorders such as Down’s Syndrome, Fragile X, autism, etc. Given the overlap of mechanisms between some of the cognitive deficits in developmental disorders and ageing-related cognitive deficits, some of the coming developments in this area of pharmacotherapy should also prove quite helpful for treating age-related dementias.

As more is learned about the time-course of dysfunction in NDDs [neurodevelopmental disorders], targeting of therapies to the existing brain state may be improved. Moreover, individuals with NDDs have multiple cognitive and behavioral disabilities, and a particular drug therapy may improve only a subset of cognitive functions. Thus, a combination of complementary drugs may offer the most benefit by addressing deficits in attention, arousal, information processing, or depression.
…
The NDDs discussed here are phenotypically diverse yet linked by common mechanisms of dysfunction, including abnormal gene dosage, imbalance among neurotransmitter systems, and local protein translation (Fig. 2). A particular NDD can be caused by mutations in multiple genes, underscoring the convergence of dysfunction in key biochemical pathways. _Source

Finally, I would like to append to this entry some material from an earlier Al Fin article, which provides a few hints of future drug targets, as well as links to related material:

AMPAkines
CREB
PDE Inhibitors(4,10)
Nicotinic Alpha-7 agonists
mGluR antagonists
5HT6 antagonists

Frontrunners in the pharmaceutical race for smarter, better memory drugs include Memory Pharmaceuticals, Cortex Pharmaceuticals, Saegis Pharmaceuticals, Helicon, Lilly, Pfizer, Wyeth, Merck, Sention and many others. The precedent of approving drugs for erectile dysfunction (ED)–a lifestyle drug–suggests that smart drugs will eventually be approved for drooping memories as well.

Further Reading:

Molecules for Memory

Nootropics

Smart Drugs: What Are the Prospects?

Shaping the Brain with Smart Drugs (Gazzaniga)

CREB and Memory (basic neuroscience)

CREB, Synapses, and Memory Disorders

Hat tip Advanced Nano and Kurzweilai.net

Al Fin Longevity

We are learning how to diagnose Alzheimer’s disease before it has begun to manifest symptoms. Genomic studies tell us who is most likely to develop the disease, and new lab tests and scanning tools can identify the disease in its earliest stages, before it starts causing apparent problems. But it is not helpful to know that a person is doomed to suffer Alzheimer’s unless you have a useful treatment or preventative. Now, such a prophylactic treatment for Alzheimer’s is being studied in Britain: Gantenerumab, a monoclonal antibody against amyloid protein.

….gantenerumab, made by Roche, is designed to be given up to four years before the disease has been diagnosed. It is aimed at people with memory problems that have caused them concern but who are still able to go about their day-to-day lives.

It contains an antibody that homes in on amyloid, the toxic protein that clogs the brain in Alzheimer’s, and speeds up its clearance from the body. In small-scale early trials on men and women who already had Alzheimer’s, it cut the amount of amyloid in the brain by up to a third in just six months, the journal Archives of Neurology reports.

It is hoped that giving it earlier would be even more effective and the drug is now being tested on 360 people in 15 countries with mild memory problems that are expected to progress to dementia. To take part in the trial, people must be aged between 50 and 89 and have memory problems that are causing them concern.

A lumbar puncture will confirm that amyloid is building up in their system, although they have yet to be diagnosed with dementia. Those taking part in the Scarlet Road Study trial will be given gantenerumab every month for two years, or a dummy drug.

…Dr Perry, a consultant neurologist at London’s Charing Cross Hospital and at the Re:Cognition Health memory clinic, said: ‘We know that the amyloid is there for many years beforehand and it is thought that if you are going to reduce the amounts to have an effect, we have got to do that before people have significant damage.’

Barbara Sahakian, a professor at Cambridge University’s psychiatry department, said she was ‘thrilled’ by the launch of the trial. She said: ‘The implications are far-reaching.
‘On a personal level, being able to stay at work and maintain your family life and all your hobbies and interests would be just fabulous. ‘There are also great implications for relatives and for society. ‘Institutional care is extremely expensive and if we had effective treatments, we could use that money in a different way.’

Dr Marie Janson of Alzheimer’s Research UK said: ‘Although research into gantenerumab is still in its early phases, initial results have looked promising.’

To find out about joining the trial, visit www.scarletroadstudy.com _DailyMail_via_ImpactLab

Advanced societies around the world are ageing quickly, due to a reduction in birthrates plus lifespans that keep extending due to better food, sanitation, health habits, and health care. As more people reach old age, Alzheimer’s disease will become more prevalent. As fewer people are born to support those who age, the disease will become a tremendous societal burden, unless effective treatments can extend a person’s lucid lifespan along with the ability to be productive to a later age.

Al Fin Longevity

We are learning how to diagnose Alzheimer’s disease before it has begun to manifest symptoms. Genomic studies tell us who is most likely to develop the disease, and new lab tests and scanning tools can identify the disease in its earliest stages, before it starts causing apparent problems. But it is not helpful to know that a person is doomed to suffer Alzheimer’s unless you have a useful treatment or preventative. Now, such a prophylactic treatment for Alzheimer’s is being studied in Britain: Gantenerumab, a monoclonal antibody against amyloid protein.

….gantenerumab, made by Roche, is designed to be given up to four years before the disease has been diagnosed. It is aimed at people with memory problems that have caused them concern but who are still able to go about their day-to-day lives.

It contains an antibody that homes in on amyloid, the toxic protein that clogs the brain in Alzheimer’s, and speeds up its clearance from the body. In small-scale early trials on men and women who already had Alzheimer’s, it cut the amount of amyloid in the brain by up to a third in just six months, the journal Archives of Neurology reports.

It is hoped that giving it earlier would be even more effective and the drug is now being tested on 360 people in 15 countries with mild memory problems that are expected to progress to dementia. To take part in the trial, people must be aged between 50 and 89 and have memory problems that are causing them concern.

A lumbar puncture will confirm that amyloid is building up in their system, although they have yet to be diagnosed with dementia. Those taking part in the Scarlet Road Study trial will be given gantenerumab every month for two years, or a dummy drug.

…Dr Perry, a consultant neurologist at London’s Charing Cross Hospital and at the Re:Cognition Health memory clinic, said: ‘We know that the amyloid is there for many years beforehand and it is thought that if you are going to reduce the amounts to have an effect, we have got to do that before people have significant damage.’

Barbara Sahakian, a professor at Cambridge University’s psychiatry department, said she was ‘thrilled’ by the launch of the trial. She said: ‘The implications are far-reaching.
‘On a personal level, being able to stay at work and maintain your family life and all your hobbies and interests would be just fabulous. ‘There are also great implications for relatives and for society. ‘Institutional care is extremely expensive and if we had effective treatments, we could use that money in a different way.’

Dr Marie Janson of Alzheimer’s Research UK said: ‘Although research into gantenerumab is still in its early phases, initial results have looked promising.’

To find out about joining the trial, visit www.scarletroadstudy.com _DailyMail_via_ImpactLab

Advanced societies around the world are ageing quickly, due to a reduction in birthrates plus lifespans that keep extending due to better food, sanitation, health habits, and health care. As more people reach old age, Alzheimer’s disease will become more prevalent. As fewer people are born to support those who age, the disease will become a tremendous societal burden, unless effective treatments can extend a person’s lucid lifespan along with the ability to be productive to a later age.

Al Fin Longevity

Research indicates that anxiety symptoms are more prevalent in elderly people than in any other age group, occurring at about twice the rate of younger adults. The types of anxiety disorders most common among the older population include generalized anxiety, mixed anxious-depressive syndrome symptoms, and phobias (often characterized by exaggerations of rational concerns). More rare are late-life onset of obsessive compulsive disorders (OCD) and panic disorders. (more…)

Depression is the most common mental health problem in the elderly. While the incidence in community-dwelling older adults is no higher than in the general population, the risk increases significantly with medical illness or institutionalization. Depression is probably the best researched of the psychiatric disorders in the elderly, with epidemiological evidence indicating that older adults have the highest suicide rate of any age group (one-fourth of all suicides are carried out by persons age 60 or older by taking sleeping pills suicide). (more…)

Compulsive hoarding disorder consists of three components: acquiring a large number of possessions, storing of items and not discarding unused objects, and keeping or storing them in such a way that it interferes with daily living, with possible severe neglect of living space. This behavior was first described in 1975 in a sample of 30 individuals, all of whom were elderly and demonstrated extreme neglect of their home, appearance, and health, and was termed Diogenes syndrome. (more…)

The current standard of clinical care for mild to moderate Alzheimer’s Disease is treatment with cholinesterase inhibitors. Four are currently available: donepezil, tacrine, rivastigmine, and galantamine. These treatments may slow cognitive decline or may reduce the emergence of new behavioral manifestations of the disease but are not considered a cure for the disease. Nevertheless, the prevalence and importance of understanding the physiological effects of these drugs in the treatment of Alzheimer’s Disease is not to be underestimated. (more…)

Neuroimaging is widely used in the evaluation of Alzheimer’s disease (AD). Traditionally, imaging in Alzheimer’s disease has been used to exclude other diseases and neurological conditions that produce similar cognitive symptoms. Recently, however, neuroimaging has been explored for its potential in predicting clinical outcomes in subjects before the onset of Alzheimer’s disease or as surrogate markers for monitoring the course of treatment. While these experimental uses tend to be more exploratory than of current clinical application, the diagnosis of Alzheimer’s disease has unquestionably been advanced with the inclusion of neuroimaging. (more…)

Identifying genetic polymorphisms that are overrepresented in Alzheimer’s Disease has proven a successful way of identifying individuals with a significant risk for AD and, in combination with imaging, may increase our ability to detect Alzheimer’s Disease in preclinical stages. In particular, discovery of the relationship between the Apolipoprotein E e4 allelle (APOE-4) allele on chromosome 19 and AD is one of the best-replicated findings in complex human genetics. APOE-4 significantly decreases the age of onset of the disease in a dosedependent manner and is associated with higher b-amyloid (Ab) plaque burden. (more…)