Brain insulin resistance in AZ
contributes to neurla cell disease
Brain insulin resistance is an abnormality in Alzheimer's disease that contributes to neural cell damage and can be detected by a new blood test, according to a multi-site study that was published October 23 in the online issue of The FASEB Journal, The Journal of the Federation of American Societies for Experimental Biology. The highly statistically significant findings were made possible by a novel technique the researchers developed for measuring brain insulin resistance in living patients.
The technique involves using neuron-derived exosomes in the blood to measure insulin resistance in the brain as an indication of early-onset Alzheimer's disease (AD). This new blood test can accurately reflect development of AD up to 10 years prior to clinical onset, the study said.
The innovative approach used in this study allowed the researchers to extract and measure phosphorylated forms of insulin receptor substrate (IRS) from isolated neural exosomes. The ability to quantify the phosphorylated forms of IRS makes it possible to evaluate insulin resistance in the central nervous system using a blood-based assay with living patients.
The study found that for patients with AD and Type 2 diabetes, the mean levels of the two extracted phosphorylated forms of insulin receptor substrate (IRS) and their ratio (known as the insulin resistance index) were significantly different than the values for the healthy control group. In addition, the researchers reported that the mean level of the brain insulin resistance index for AD was significantly higher than for either Type 2 diabetes or frontotemporal dementia (FTD). 100% of the patients with AD in the study were correctly classified with the researcher's technique, as were 97.5% of patients with type 2 diabetes.
"This study shows that insulin resistance is a major central nervous system metabolic abnormality in AD that contributes to neural cell damage," said Ed Goetzl, the senior author on the study and the originator of the exosome isolation technique. "As insulin resistance is a known condition in Type 2 diabetes mellitus and is treatable with several classes of existing drugs, these treatments may be useful as part of a multi-agent program for AD."
The exosome-based technology used in the study will be further developed by NanoSomiX, a sponsor of the study, to produce a commercially available blood-based assay for researchers in academia and pharmaceutical companies. The assay will provide valuable information to those that are developing drugs for AD by using a routine and cost effective approach for early identification of subjects for inclusion in clinical trials. NanoSomiX will also be introducing an exosome-based blood test for p-tau, a biomarker for AD that is currently detected only in cerebrospinal fluid and with PET scans, in November.
IPD article estimates risk of mortality
attributional to incident AD dementia
In Article Review in the Incidence and Prevalence Database (IPD) estimated the risk of mortality attributable to incident Alzheimer disease (AD) dementia in 2 community-based cohort studies and estimated the number of deaths attributable to AD dementia in the U.S. Two ongoing cohort studies of aging and AD, the Religious Orders Study and the Rush Memory and Aging Project, provided the data for these analyses. In both studies, participants without known dementia at baseline agreed to annual detailed clinical evaluation and brain donation at the time of death.
From September 1997 through February 2013, 1,574 persons completed a baseline evaluation. Clinical and diagnostic procedures are identical across the 2 studies, allowing them to be pooled for analysis. Follow-up among living participants exceeds 90%. Although participants in these studies did not have known dementia at the time of recruitment, a small portion (n = 176, 6.4%) were diagnosed with dementia upon baseline clinical examination and were excluded from these analyses, leaving 2,566 for analysis. Population attributable risk percentage (PAR%) was calculated to estimate the percentage of total mortality risk for the cohort that could be considered attributable to an incident diagnosis of AD dementia.
Incidence and survival (U.S.): Over an average of 8.0 years of follow-up per person, 559 (21.8%) persons were diagnosed with AD dementia, 31 (1.2%) were diagnosed with other forms of dementia, and 1,090 (42.4%) died. The mean age at incident AD dementia diagnosis was 86.53 years. The median survival time from AD dementia diagnosis to death from Kaplan-Meier curves for participants who developed AD dementia was 3.8 years overall and was related to age at diagnosis. Median survival was 4.4 years for persons aged 75-84 at AD dementia diagnosis (n = 182) and 3.2 for persons aged 85 and older at AD dementia diagnosis (n = 356).
Mortality: Crude PAR% was 16.9% for ages 75-84 and 30.2% for ages 85 and older. Applying the age-specific estimates of PAR% to the numbers of deaths in the United States in 10-year age groups gave a figure of 503,400 excess deaths after a diagnosis of AD dementia in 2010 for Americans aged 75 and older.
In this study of older adults without dementia at the beginning of observation, the development of AD dementia significantly contributed to the burden of mortality. The rate of death was 3 to 4 times higher after a diagnosis of AD dementia and more than one-third of all deaths were attributable to AD dementia. This translates into a figure of more than 500,000 deaths attributable to AD dementia in the U.S. population in 2010. Overall, the data indicate that the proportion of older persons who die of AD is much higher than the number indicated by death certificates, which is less than 5% of all deaths in the elderly (see Article Review: "Contribution of Alzheimer Disease to Mortality in the United States" as cited in the IPD).
optogenetcially-enabled is possible
A brain-computer-interphase that is optogenetically-enabled is one of the most fantastic technologies we might envision today. It is likely that its full power could only be realized under the guidance of accurate maps of the brain's activity and connections. Creating these maps—or more likely, these dynamic models—will require tools that have scarcely been described let alone implemented. Among the most tantalizing ideas yet to emerge in this vein are probably what the "Kording-Church DNA tickertapes" which are based on modified DNA polymerases to record activity, and also "Zador neural barcodes" that are based on modified viruses which record connections.
When these two concepts were first described a few years ago, the initial excitement over them quickly gave way to the harsh realities of their complexity. Getting viruses to generate recombinant barcode labels for neuronal connections seems like pie in the sky when we can hardly get them to transport themselves to desired locations and express desired proteins without doing undue harm to cells. Tony Zador's group has now taken a big practical step towards contructing viral tools which use targeted gene expression to map neural circuits. Their latest work, published in Frontiers in Neuroanatomy, describes how they modified a pseudorabies virus (PRV) to efficiently navigate the nervous system and genetically tag select neurons.
Several kinds of viruses can invade the brain and turn it into their own private playground. Once past the blood brain barrier (BBB) , and safe from the normal immune sentinels that patrol the peripheral circulation, they bud across synapses within lipid bubbles and then hitch rides to more centralized hubs like winter enthusiasts on a retrograde axonal ski lift. The innate immune cells of the brain (the microglia), are generally powerless against viruses tucked away inside cells. In some cases of infection, drugs that permeabilize the BBB to let more capable immune agents enter the brain can be injected as a last resort, but the process is not very specific.
The PRV vector used by Zador's group has several advantages for mapping neurons compared to other potential viral vectors. One cousin of the PSV virus, namely a mutant of the HSV-1 virus, has been successfully used by others for retrogradely targeting particular neuronal populations. The main problem the HSV-1, is that like the brain-mapping molecular tickertapes, this guy is a proprietary and patented virus. Another flexible vector is a modified vesicular stomatitis virus (VSV-G). It can be readily switched between retrograde and anterograde transport modes with a change to a single gene. Unfortunately, many of the usual suspects that limit all things viral – namely infection inefficiency, cytotoxicity, limited payload capacity, safety concerns, availability, and unpredictable tropism – are all factors with VSV-G.
A brain-computer-interphase that is optogenetically-enabled is one of the most fantastic technologies we might envision today. It is likely that its full power could only be realized under the guidance of accurate maps of the brain's activity and connections. Creating these maps – or more likely, these dynamic models – will require tools that have scarcely been described let alone implemented. Among the most tantalizing ideas yet to emerge in this vein are probably what the "Kording-Church DNA tickertapes" which are based on modified DNA polymerases to record activity, and also "Zador neural barcodes" that are based on modified viruses which record connections.
The man with a thousand brains
Forty million people worldwide are living with Alzheimer's and this is only set to increase. But tiny brains grown in culture could help scientists learn more about this mysterious disease – and test new drugs.
It sounds like something from a 1950s' B-movie: scientists growing brains in the lab. It brings to mind images of dimly lit, cobweb-filled rooms with brains pulsating in glass tanks.
The truth, of course, is far less gothic. The Wellcome Trust/Cancer Research UK Gurdon Institute, where the research is taking place, is light, airy and hi-tech. But although Rick Livesey, who leads the study, does not like to call them 'mini-brains', that is in essence what they are: clusters of millions of nerve cells, electrically active and networked to each other, and no bigger than a freckle. What makes these 'brains' particularly useful is that they are diseased – they have Alzheimer's.
The standard way to study a disease is to use animals. Crudely speaking, you insert a human disease gene or series of genes into a mouse and observe the mechanisms that lead the animal to develop the disease. This approach is useful for asking specific questions, but doesn't show the disease process in a cohesive way. It can lead to the development of drugs that treat the disease in mice but fail when it comes to humans.
Instead, Livesey has turned to stem cells, building on research that won Sir John Gurdon, the man who gave his name to the institute at which Livesey now works, a Nobel Prize in 2012.