Tag Archives: Aging

ReigershoeveAt a recent meeting in Amsterdam, members of the JPND Management Board, which is the decision-making body of JPND, were invited to tour Reigershoeve, a patient-centered residential ‘care farm’ for people living with dementia.

Located in Heemskerk, about a half hour northwest of Amsterdam, Reigershoeve is home to 27 people living with dementia, according to Dieneke Smit, who started the care farm with her father, Henk Smit. The property includes a farm with animals, an art studio, a greenhouse and vast gardens. Residents are grouped into smaller homes, and are encouraged to help cook, clean and maintain the property in a community-living environment.

Reigershoeve

Reigershoeve

Dieneke Smit, who founded Reigershoeve with her father, Henk Smit, and Bart Kooiman, a Programme officer at ZonMw

Dieneke Smit, who founded Reigershoeve with her father, Henk Smit, and Bart Kooiman, a Programme officer at ZonMw.

Reigershoeve

Reigershoeve

Reigershoeve

Amsterdam_201605_17

Dieneke Smit leading a guided tour of the grounds at Reigershoeve.

Reigershoeve

The Reigershoeve farm includes pigs and donkeys.

Reigershoeve

Thank you to Dieneke and the rest of the Reigershoeve community for welcoming the JPND Management Board and showing us around! To learn more about Reigershoeve, visit the website.

Researchers have shown how brain connections, or synapses, are lost early in Alzheimer’s disease and demonstrated that the process starts — and could potentially be halted — before telltale plaques accumulate in the brain. Their work, published online by Science, suggests new therapeutic targets to preserve cognitive function early in Alzheimer’s disease.

The researchers show in multiple Alzheimer’s mouse models that mechanisms similar to those used to “prune” excess synapses in the healthy developing brain are wrongly activated later in life. By blocking these mechanisms, they were able to reduce synapse loss in the mice.

Currently, there are five FDA-approved drugs for Alzheimer’s, but these only boost cognition temporarily and do not address the root causes of cognitive impairment in Alzheimer’s. Many newer drugs in the pipeline seek to eliminate amyloid plaque deposits or reduce inflammation in the brain, but the new research from Boston Children’s suggests that Alzheimer’s could be targeted much earlier, before these pathologic changes occur.

“Synapse loss is a strong correlate of cognitive decline,” says Beth Stevens, assistant professor in the Department of Neurology at Boston Children’s, senior investigator on the study and a recent recipient of the MacArthur “genius” grant. “We’re trying to go back to the very beginning and see how synapse loss starts.”

The researchers looked at Alzheimer’s — a disease of aging — through an unusual lens: normal brain development in infancy and childhood. Through years of research, the Stevens lab has shown that normal developing brains have a process to “prune” synapses that aren’t needed as they build their circuitry.

“Understanding a normal developmental process deeply has provided us with novel insight into how to protect synapses in Alzheimer’s and potentially a host of other diseases,” says Stevens, noting that synapse loss also occurs in frontotemporal dementia, Huntington’s disease, schizophrenia, glaucoma and other conditions.

In the Alzheimer’s mouse models, the team showed that synapse loss requires the activation of a protein called C1q, which “tags” synapses for elimination. Immune cells in the brain called microglia then “eat” the synapses — similar to what occurs during normal brain development. In the mice, C1q became more abundant around vulnerable synapses before amyloid plaque deposits could be observed.

When Stevens and colleagues blocked C1q, a downstream protein called C3, or the C3 receptor on microglia, synapse loss did not occur.

“Microglia and complement are already known to be involved in Alzheimer’s disease, but they have been largely regarded as a secondary event related to plaque-related neuroinflammation, a prominent feature in progressed stages of Alzheimer’s,” notes Soyon Hong, the Science paper’s first author. “Our study challenges this view and provides evidence that complement and microglia are involved much earlier in the disease process, when synapses are already vulnerable, and could potentially be targeted to preserve synaptic health.”

A human form of the antibody Stevens and Hong used to block C1q, known as ANX-005, is in early therapeutic development with Annexon Biosciences (San Francisco) and is being advanced into the clinic. The researchers believe it has potential to be used someday to protect against synapse loss in a variety of neurodegenerative diseases.

“One of the things this study highlights is the need to look for biomarkers for synapse loss and dysfunction,” says Hong. “As in cancer, if you treat people at a later stage of Alzheimer’s, it may already be too late.”

The researchers also found that the beta-amyloid protein, C1q and microglia work together to cause synapse loss in the early stages of Alzheimer’s. The oligomeric form of beta-amyloid (multiple units of beta-amyloid strung together) is already known to be toxic to synapses even before it forms plaque deposits, but the study showed that C1q is necessary for this effect. The converse was also true: microglia engulfed synapses only when oligomeric beta-amyloid was present.

Source: Reprinted from materials provided by Boston Children’s Hospital
Paper: “Complement and microglia mediate early synapse loss in Alzheimer mouse models”

Researchers have used a non-invasive method of observing how the process leading to Parkinson’s disease takes place at the nanoscale, and identified the point in the process at which proteins in the brain become toxic, eventually leading to the death of brain cells.

The results suggest that the same protein can either cause, or protect against, the toxic effects that lead to the death of brain cells, depending on the specific structural form it takes, and that toxic effects take hold when there is an imbalance of the level of protein in its natural form in a cell. The work could help unravel how and why people develop Parkinson’s, and aid in the search for potential treatments. The study is published in the journal Proceedings of the National Academy of Sciences.

Using super-resolution microscopy, researchers were able to observe the behaviour of different types of alpha-synuclein, a protein closely associated with Parkinson’s disease, in order to find how it affects neurons, and at what point it becomes toxic.

Parkinson’s disease is one of a number of neurodegenerative diseases caused when naturally occurring proteins fold into the wrong shape and stick together with other proteins, eventually forming thin filament-like structures called amyloid fibrils. These amyloid deposits of aggregated alpha-synuclein, also known as Lewy bodies, are the hallmark of Parkinson’s disease.

Parkinson’s disease is the second-most common neurodegenerative disease worldwide (after Alzheimer’s disease). More than seven million people worldwide have the disease. Symptoms include muscle tremors, stiffness and difficulty walking. Dementia is common in later stages of the disease.

The researchers used different forms of alpha-synuclein and observed their behaviour in neurons from rats. They were then able to correlate what they saw with the amount of toxicity that was present.

They found that when they added alpha-synuclein fibrils to the neurons, they interacted with alpha-synuclein protein that was already in the cell, and no toxic effects were present.

The researchers then observed that by adding the soluble form of alpha-synuclein together with amyloid fibrils, the toxic effect of the former could be overcome. It appeared that the amyloid fibrils acted like magnets for the soluble protein and mopped up the soluble protein pool, shielding against the associated toxic effects.

The research shows how important it is to fully understand the processes at work behind neurodegenerative diseases, so that the right step in the process can be targeted.

Source: Adapted from materials provided by the University of Cambridge
“Nanoscopic insights into seeding mechanisms and toxicity of α-synuclein species in neurons”

Researchers are studying the causes of premature ageing of neurons in Parkinson’s patients with a defective DJ1 (PARK7) gene. The genetic defect causes changes in the cellular metabolism meaning that neurons are subjected to oxidative stress and an increased immune response in the brain. The study has just been published in the scientific journal Neurobiology of Disease.

Parkinson’s disease, the second most common neurodegenerative disease, has genetic causes in 15% of cases. Premature ageing of dopaminergic neurons in the substantia nigra in the brain is the reason for the motor symptoms that characterise this disease. However, how this happens is not yet fully understood.

In the current study, researchers looking for the answer in metabolism investigated a specific form of Parkinson’s disease with a defective DJ1 gene and discovered that two key metabolic pathways are affected.

The research team was also able to show that mutations in the DJ1 gene can also negatively affect other cells in the brain. Microglial cells, which are responsible for the immune reaction in the brain, become ‘hyperactive’ when the DJ1 gene is defective.

Interestingly, the researchers were able to determine metabolic changes not only in the brain’s immune cells but also in the blood of Parkinson’s patients with mutant DJ1. This could lead to new diagnostic avenues in the future.

The next step will involve investigating how affected metabolic pathways can be influenced using drugs. The changes described in glutamine and serine metabolic processes could thus be used to develop novel approaches for treating Parkinson’s.

Source: University of Luxembourg

New research shows for the first time that PET scans can track the progressive stages of Alzheimer’s disease in cognitively normal adults, a key advance in the early diagnosis and staging of the neurodegenerative disorder.

In the process, the scientists also obtained important clues about two Alzheimer’s-linked proteins – tau and beta-amyloid – and how they relate to each other.

The findings, published in the journal Neuron, come from positron emission tomography (PET) of 53 adults. Five were young adults aged 20-26, 33 were cognitively healthy adults aged 64-90 and 15 were patients aged 53-77 who had been diagnosed with probable Alzheimer’s dementia.

PET scans are used to detect early signs of disease by looking at cellular-level changes in organs and tissue. The results of the scans in this study paralleled Braak neuropathological stages, which range from one to six, describing the degree of tau protein accumulation in the brain.

The findings also shed light on the nature of tau and amyloid protein deposits in the aging brain. For many years, the accumulation of beta amyloid plaques was considered the primary culprit in Alzheimer’s disease. Over the past decade, however, tau, a microtubule protein important in maintaining the structure of neurons, has emerged as a major player. When the tau protein gets tangled and twisted, its ability to support synaptic connections becomes impaired.

While a number of symptoms exist that signal Alzheimer’s disease, a definitive diagnosis has been possible only through an examination of the brain after the patient has died. The availability of amyloid imaging for the past decade has improved this situation, but how Alzheimer’s developed as a result of amyloid remains a mystery. Studies done in autopsies linked the development of symptoms to the deposition of the tau protein.

Through the PET scans, the researchers confirmed that with advancing age, tau protein accumulated in the medial temporal lobe — home to the hippocampus and the memory center of the brain.

The study revealed that higher levels of tau in the medial temporal lobe was associated with greater declines in episodic memory, the type of memory used to code new information. The researchers tested episodic memory by asking subjects to recall a list of words viewed 20 minutes earlier.

One question yet to be answered is why so many people have tau in their medial temporal lobe yet never go on to develop Alzheimer’s. Likewise, adults may have beta amyloid in their brains and yet be cognitively healthy.

While higher levels of tau in the medial temporal lobe was linked to more problems with episodic memory, it was when tau spread outside this region to other parts of the brain, such as the neocortex, that researchers saw more serious declines in global cognitive function. Significantly, they found that tau’s spread outside the medial temporal lobe was connected to the presence of amyloid plaques in the brain.

What the study does indicate is that tau imaging could become an important tool in helping to develop therapeutic approaches that target the correct protein — either amyloid or tau — depending on the disease stage.

Source: Sarah Yang, UC Berkeley

The Active and Assisted Living Programme (AAL), which aims to improve the conditions of life for older adults through the use information and communication technology (ICT), has opened its 2016 call, Living well with dementia.

The objective of the call is to advance the contribution of ICT to integrated solutions that enable the well being of people living with dementia and their communities, including their family, caregivers, neighbourhood, service providers and care system. The call aims to support innovative, transnational and multi-disciplinary collaborative projects with a clear route to market and added value for the different types of end users. A key priority underlying this challenge will be to bring together technologies and services to create ICT-based solutions addressing the specific aspirations and challenges of people living with dementia and their communities.

The submission deadline is 26 May 2016, 5PM CET. To learn more about the call or to register to watch the live webcast on 8 March, please visit the AAL website.

Men taking androgen deprivation therapy (ADT) for prostate cancer were almost twice as likely to be diagnosed with Alzheimer’s disease in the years that followed than those who didn’t undergo the therapy, an analysis of medical records from two large hospital systems has shown. Men with the longest durations of ADT were even more likely to be diagnosed with Alzheimer’s disease.

The findings, published in the Journal of Clinical Oncology, do not prove that ADT increases the risk of Alzheimer’s disease. But the authors say they clearly point to that possibility, and are consistent with other evidence that low levels of testosterone may weaken the aging brain’s resistance to Alzheimer’s.

For the study, researchers evaluated two large sets of medical records, one from the Stanford health system and the other from Mt. Sinai Hospital in New York City. The researchers scanned the records of 1.8 million patients from Stanford Health Care, and, through a prior institutional research agreement, 3.7 million patients from Mount Sinai Hospital.

Among this cohort, they identified about 9,000 prostate cancer patients at each institution, 16,888 of whom had non-metastatic prostate cancer. A total of 2,397 had been treated with androgen deprivation therapy. The researchers compared these ADT patients with a control group of non-ADT prostate cancer patients, matched according to age and other factors.

Using two different methods of statistical analysis, the team showed that the ADT group, compared to the control group, had significantly more Alzheimer’s diagnoses in the years following the initiation of androgen-lowering therapy. By the most sophisticated measure, members of the ADT group were about 88 percent more likely to get Alzheimer’s.

Source: Penn Medicine

A study of the brains of mice shows that structural deterioration associated with old age can be prevented by long-term aerobic exercise starting in mid-life, according to a research article published in PLOS Biology. Researchers found that structural changes that make the blood-brain barrier leaky and result in inflammation of brain tissues in old mice can be mitigated by allowing the animals to run regularly, so providing a potential explanation for the beneficial effects of exercise on dementia in humans.

Physical activity is already known to ameliorate the cognitive decline and sensorimotor deficits seen in old age in humans as well as in mice. To investigate the impact of long-term physical exercise on the brain changes seen in the aging mice, the researchers provided the animals with a running wheel from 12 months old (equivalent to middle aged in humans) and assessed their brains at 18 months (equivalent to ~60yrs old in humans, when the risk of Alzheimer’s disease is greatly increased). Young and old mice alike ran about two miles per night, and this physical activity improved the ability and motivation of the old mice to engage in the typical spontaneous behaviors that seem to be affected by aging. This exercise significantly reduced age-related pericyte loss in the brain cortex and improved other indicators of dysfunction of the vascular system and blood-brain barrier.

Source: PLOS Biology